Tuesday, February 18, 2014

Are clinical trials outsourced to the developing world exploitative?

by Roger Stanev

The number of clinical trials outsourced by pharmaceutical companies to developing countries has surged since the mid-1990s. Current estimates suggest that 40% of the total number of trials are now conducted in less developed regions of the world, e.g., India, Brazil, Mexico, South Africa, and Eastern Europe. The situation has raised important questions about the ethics of clinical research, including the question of whether or not such trials are exploitative.

On one side of the debate, some argue that outsourcing is not exploitative because it brings global benefits by allowing pharmaceutical companies to test new drugs more quickly, cheaply and effectively than they can in the U.S. (or other developed countries). It is cited, for instance, that the average cost of running a phase-III clinical trial in developing countries is approximately 70% cheaper than in the U.S., and that this is beneficial because cheaper research leads to cheaper drugs, which would mean more affordable drugs for impoverished populations. Proponents of outsourcing also argue that it transfers resources and expertise to less developed regions of the world while also providing researchers with access to a larger, more genetically diverse population, as well as ‘clean-patients,’ i.e., participants who are less likely to have been treated with other drugs or by other clinical trials.

On the other side of the debate, some argue that outsourced trials are exploitative because these populations are poor, with low levels of literacy, and often powerless to defend their own interests; the trials are exploitative because they exploit the vulnerability of people in the developing world. There is also a concern that, because necessary legal and ethical institutions safeguarding the interests of trial participants are not in place in many of these countries—e.g., less stringent ethical reviews, the under-reporting of side effects, and lower risks of litigation—there is an increased likelihood of research ethical misconduct.

If we suppose, as Emanuel et al does, that “the fundamental ethical challenge of all research with humans is to avoid exploitation”, then it is reasonable to say that our first order of business should be determining whether any outsourced clinical trial is exploitative. (In this case, we should focus on the moral sense of ‘exploitation’ as wrongful or impermissible exploitation.) What makes a clinical trial wrongfully exploitative? Consider accounts of exploitation that appear to give us truth conditions for wrongful exploitation claims, such as: a clinical trial is exploitative if the distribution of risks and potential benefits to trial participants is unfair. For example, if potential trial participants take most of the risks (e.g., possible serious side effects, undue burdens) but little expected benefits (e.g., cannot afford the drug if proven effective), whereas Glaxo Smith Kline (GSK) takes little risks but high potential benefits (e.g., high profit margins under low risk), then the trial is exploitative. So, if the drug being tested is not likely to be affordable in the host country or if the health care infrastructure cannot support its proper distribution and use, then it is exploitative. It would be exploitative to ask individuals in a developing country to participate in research, since they will not enjoy any of its potential benefits. But is this right?

Let’s look at a specific case. In the 1990s, GSK conducted clinical trials of a short-regimen of AZT in Uganda. These placebo controlled trials assessed whether lower doses of AZT than those used in rich countries (such as the U.S.) could reduce the rate of mother-to-child transmission of HIV. The existing normal regimen of AZT which was previously evaluated and approved in the U.S. (protocol 076) was deemed too costly for needy African populations. The average cost for the full regimen was over $1K per woman per year, whereas the annual health budget of African countries was under $10 per person—Uganda’s health budget at the time was estimated to be under $3 per person per year.

Even though GSK was taking advantage of the unfair situation in which trial participants found themselves in Uganda (i.e., poor and without routine access to healthcare), GSK could argue that it was not taking unfair advantage of the trial participants per se. They could further argue that, if the pharmaceutical market in which GSK and Ugandans operate is competitive, GSK does not exploit Ugandans if GSK pays Ugandans the ‘market’ price to participate in the trials, and that Ugandan participants should complain to their government representatives, not GSK, if their country cannot afford to pay for the healthcare infrastructure required for its citizens to afford and access the drug’s potential benefits. Moreover, what if GSK wanted to pay for the health care infrastructure required for Ugandans, but said it couldn’t because of alleged highly competitive market GSK finds itself in?

But, in my opinion, this trial was exploitative because the Ugandans were unable to afford and access the drugs they tested. Even if competitive market pressures made it unfeasible for GSK to pay for more, the trial was still exploitative. A clinical trial outsourced to the developing world is exploitative unless the trial’s sponsors provide actual benefits to the vulnerable population, including raising the host country’s health infrastructure baseline—raising it in ways that make the potential drug affordable and accessible to the needy.


Roger Stanev
Department of Philosophy
University of South Florida

12 comments:

  1. Roger, thanks for this interesting piece. Being entirely unfamiliar with this area, I don't really understand why the exploitativeness of a clinical trial should depend on whether the population in which the trial is being run would be in a position to benefit from the treatment being tested. It seems to me that the concept of unfair exploitation is best restricted to situations in which people in desperate circumstances are taken advantage of in a way that is morally offensive. The obvious ones would be that they are lied to about the risks of what they are doing, or about what is actually being done to them, as in the Tuskegee syphilis trials. Or when their participation is clearly non voluntary. But I don't see anything essentially exploitative about adequately compensated informed participation in trials that the population at large just doesn't stand to benefit from.. Suppose, for example, that the treatment being tested isn't a particularly significant problem in this area of the world, or that it is something like lasik surgery which is expensive and purely elective even in our part of the world. I do agree that it is morally troubling to hear about a treatment being tested on a population that is truly suffering from the condition being treated, but which is permanently beyond their ability to access But I'm not sure it is any more troubling or more exploitative than employing people truly suffering from poverty to manufacture products they will never be able to purchase. In fact, that sort of is what it is.

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    1. Randy, thank you for the thoughtful comments. It's a hard one. But when you say that you “do agree that it is morally troubling” we are in agreement, though I want to go further and say it is also wrongfully exploitative. It is wrongfully exploitative because it takes unfair advantage of the situation: the dire need of the Ugandans, making their population both appropriate research subjects and particularly vulnerable. And unless this link between need and vulnerability is weaken or broken, it is wrongfully exploitative. Making the benefits of the research both accessible and affordable (e.g., the treatment, the knowledge obtained from doing the research) is a way to weaker the link between need and vulnerability.

      As for your analogy with Marx’s exploitation model, and the testing of elective medical interventions (e.g., lasik), I’m not sure they are emblematic of the current state of outsourced clinical trials in developed countries. But that's ok, if they are, if the relationship trial-sponsor – population to which such studies give rise to are exploitative, for instance, by reinforcing pernicious forms of inequality, then my response is that they are also wrongfully exploitative--although less so than cases where the population is truly suffering from the condition being treated. But I need to think more about these elective cases. Thank you.

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  2. Thanks for this, Roger. You propose an account of (wrongful) exploitation as something like taking unfair advantage of another’s vulnerability. You suggest, furthermore, either (or both) that the unfairness (and wrongfulness) is tied to the distribution of risks and benefits or to the vulnerability of the exploited party. Some say that getting the exploited party’s consent in this rebuts the charge of wrongfulness, but this is where the exploited party’s vulnerability does its work. Even rational, uncoerced consent maybe isn't appropriately voluntary if given in conditions of (relatively extreme?) vulnerability. All this seems right to me.

    But even if it is, there could still be reason to distinguish between ‘harmful’ and ‘beneficial’ exploitation. The idea is that one can take unfair advantage of another’s vulnerability in ways that either make the exploited party worse off or better off. Both ways seem to me, at a minumum, morally dubious. But I’m worried about policies that treat them both the same. Surely, we’d want to forbid harmful exploitation. But imagine a case of beneficial exploitation where you’re in a position to squash the deal. Wouldn't the exploited party be just *begging* you not to do that?

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    1. Swan, thank you for the comments. We seem to be in agreement. Yet, as for reasons to distinguish ‘harmful’ from ‘beneficial’ exploitation, let’s see how the distinction works. So, wrongful exploitation is unfair. ‘Harmful’ exploitation is wrongful exploitation where trial participants were not left better off (but GSK was). It also includes cases where it appears that subjects have given voluntary consent but in fact the consent was coerced. ‘Beneficial’ exploitation, on the other hand, both parties are left better off. But are vulnerable trial participants better off than what? Better off than what would otherwise have been, or better off than what should have been? Suppose it was mutually beneficial, yet the exploitation was not mutual. It might be a bit harder to explain why we might want to prohibit ‘beneficial’ exploitation, I agree. Nonetheless, I think we should be careful about ‘participants should not be denied a potential treatment that would otherwise not be available to them [in light of the realities in the country]’ vs. ‘should not be denied a potential treatment that should otherwise be available to them.’ But I think you raise a good point about being careful about prohibiting certain exploitation vs. refusing to enforce a particular deal.

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  3. Thanks for this piece, Roger. Really interesting stuff. I'm also skeptical that the real heart of exploitation is about whether the population that is researched ultimately has access to the drugs or benefits that are produced. Lots of clinical trials have negative results and it is discovered that some drug or procedure doesn't have any benefit at all. So neither the tested upon population nor anyone else would derive any benefit from that particular line of research, but pretty clearly the company could be exploiting them. On the flip side, you could have a drug trial in one of these countries that clearly exploits people and that ultimately produces a beneficial drug that they do get access too. That is, I can imagine cases where the subjects are exploited even when the population at large derives benefits from that exploitation. What strikes me as more central is that a company like GSK is pretty clearly motivated to go to one of these countries not just to save money, but to evade the more stringent regulatory structure that is in place to protect people from exploitation in the United States. It's not my area, but it seems like an account of exploitation should include the victim engaging in the activity somewhat voluntarily (otherwise it turns into slavery, etc.), and the activity is motivated by the victim's basic human needs, but the activity is ultimately detrimental to the victim's overall well-being, or at least falls below a threshold for being beneficial. Cool topic.

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  4. Thank you for another great comment. Matt, I agree with much you said here. But most importantly, I think you're right, there are more reasons to find these trials exploitative than simply the distribution of risks and benefits. And more scenarios of taking unfair advantage of research subjects.

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  5. Suppose current exploitation produces possibilities that would otherwise not exist. There are, after all, cases where a change in the modal properties of a state of affairs yields a change in its moral properties. Risks are examples of such changes

    Drug 'exclusivity' - the legal prohibition on developing generic versions of a drug - is time-limited. As I understand it, lots of developing countries go on to produce cheaper generic versions. That's possible, of course, only if the original drug gets tested.
    So the exploitative testing produces possibilities that a refusal of the testing would not.
    Arguably that makes a moral difference.

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    1. Tom, thank you so much for these comments. Current exploitation produces possibilities that would otherwise not exist. I agree. Exploitative testing produces possibilities (e.g., generic drug) that a refusal of the testing would not. But it also produces possibilities contributing to even further exploitation that a refusal of the testing would not. One example is ‘evergreening’: new legal-business strategies used by pharmaceutical patent holders to extend their high rent-earning property rights. One such strategy is the making of incremental patentable changes to a highly profitable drug in order to avoid losing its monopoly (supragenerics). In a recent case in India, its supreme court decided to prevent Novartis from getting protection on an updated (expensive) cancer drug because it thought the drug didn’t represent any real enhancement over its previous version. That is, a 1% efficacy update is not an advance worthy of further 7 year patent protection—I mean, not in their backyard. I can think of other changes in the modal properties of drugs and patents, making a moral difference, e.g., today compulsory licenses for public health reasons. What other changes in modal properties you had in mind? Data exclusivity of drugs is another example you mention. It prevents prices from falling due to generic drug competition, making it more expensive for the poor and vulnerable to gain access to important anti-retroviral drugs. Many thanks for the comments.

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  6. Roger, I wonder whether you think a taste test for a new soda would be (wrongly) exploitative if the people tested would not be able to afford the new drink anyway. I suspect you would not think this. Is it important, then, that there is a (serious) risk involved in testing these new drugs in places like Uganda without promising the Ugandans any of the eventual benefits of the drug?

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    1. Russell, it depends. We have to be careful here. When I’m referring to risk, I am not limiting it to narrow specialist notions typically expressed in clinical trials report. To be fair, there are several interpretations of risk (and risk analysis) found in biomedical research. The most common uses of risk have specialized meanings, reflecting conventions and interests of particular sub-disciplines, which are set by those in control of study design and report. Examples of common technical meanings of risk: (1) an unwanted event which may or may not occur, e.g. “lung cancer is one of the major risks that affect smokers”; (2) the cause of an unwanted event which may or may not occur, e.g. “smoking is by far the most important health risk in industrialized countries”; (3) the probability of an unwanted event which may or may not occur, e.g. “there is evidence that the risk of having one’s life shortened by smoking is as high as 50%”; (4) the statistical expectation value of an unwanted event which may or may not occur, e.g. “the total risk from smoking is higher than that from any other cause that has been analyzed by risk analysts”; (5) the fact that a decision is made under conditions of known probabilities, as in a “decision under risk” as opposed to a “decision under uncertainty”, e.g. “the probabilities of various smoking-related diseases are so well-known that a decision whether or not to smoke can be classified as a decision under risk”. Thus, when I’m referring to (serious) risks involved in testing new drugs in places like Uganda, I want to account for the risks according to the Ugandans too, not simply the risks according to trial sponsors. What counts as risk and serious risk in a trial should be open to negotiation and reconstruction, and represent the views of potential trial participants, e.g., HIV+ pregnant Ugandan mothers.

      As for the people testing soda scenario, what’s the context? What sort of situation are the taste testers in? If the people testing soda have no realistic alternative other than subject to soda testing all day long, in order to receive a wage in order to survive, then it is also (wrongfully) exploitative. Although testers neither need access to nor afford the soda in order to survive (unlike the Ugandans who need access to and be able to afford the medical intervention), soda testers nevertheless needed soda testing in order to survive. Shouldn’t this be considered exploitation too? I think it should. Many thanks for your comments and question.

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