Obligations: Not to Harm or to Maximise Outcome?

In “Clinical Trials Offshored: On Private Sector Science and Public Sector Health” Adriana Petryna discusses some of the moral concerns involved in the testing of pharmaceuticals on poorer and more vulnerable groups. The point I would like to discuss is whether the use of placebos is acceptable in offshore trials; when a gold standard exists yet is not otherwise available to the trial participants.

There is debate as to whether CRO’s should treat offshore trial participants with the same ethical standards as we would in first world western countries, or whether it is acceptable to provide different standards based on the location of the study. The issue is whether subjects in the control group should be given placebos, or whether they should be given the best available treatment already demonstrated to be effective. While it would be morally beneficial to use the best available treatment, whether or not CRO’s should be obligated to do so is another matter. I am going to argue that it is acceptable for CRO’s to use placebos in offshore trials.

The first reason why the use of placebos is acceptable is because; without them, the study might not get done. If a company has to compare its ‘me-too’ drug against the current standard, the likelihood of efficacy is much lower than if they were to compare it to a placebo. Because companies have little motivation in demonstrating that their drug works as well as another; the study might not get done altogether. Assuming that these clinical trials are good for the trial participants, and the long term medical infrastructure of the region, we can acknowledge that not having a study at all is significantly worse than having a less than ideal study.

The next reason involves cost. The price of the gold standard drug might be too expensive for rival drug companies to be willing to pay for them; also potentially causing the study to not be done at all. I argue that if it is insisted that the placebo be substituted with the gold standard, it should not be up to the CRO or the drug company financing the study to pay the additional cost. Perhaps the maker of the gold standard could provide it; or the government in which the study is taking place.

The last reason why the use of placebos is acceptable in some offshore clinical trials is simply because the participants are not made worse off by not getting the gold standard drug. Because their alternative is no treatment at all, a 50% shot at getting a me-too drug can only benefit them, and whilst not ideal; they surely cannot claim to have been made worse off by the study.

Because pharmaceutical companies and CROs are profit driven companies; we should accept that their obligations are merely not to harm their trial participants; as opposed to being obligated to maximise their well-being.

 

Clinical Trials and Informed Consent

          In “Ready to Recruit or Ready to Consent Populations?”, Jill A. Fisher explores a number of contextual features surrounding the recruitment of clinical trial participants in the United States.  In light of these features, she argues that the moral significance of seeking “informed consent” from potential participants is largely undermined.  Her main point seems to be that potential participants often decide in advance whether or not to join a trial, and that informed consent forms subsequently presented to them will typically have little impact on the decision that’s been made.  This is so in part because the public is provided with access to information beforehand in the form of (often misleading) trial advertisements that tend to be much easier to understand than the long and somewhat inaccessible forms they’re subsequently presented with.  However, another major factor is that the targeted participants are often disadvantaged members of the population who, due to their financial difficulties, tend to be more worried about either supplementing their income or receiving free medical care than about potential risks mentioned in informed consent forms. 

          Though Fisher brings up some important problems surrounding clinical trial recruitment practices, it seems to me she ought to be drawing more attention to the limitations on trial participant’s positive freedom and less attention to the fact that they tend to make up their minds on the basis of slanted advertisements.  In so far as the latter is a problem, it could largely be solved by the sort of reform proposals that she mentions in association with those who think informed consent procedures would be a valuable source of moral legitimacy if sufficiently modified.  Were some of the suggested modifications to take place, then it might be reasonable to conclude that such procedures would be able to correct any mistaken impressions provided by advertisements designed to draw participants in, thereby transforming ill informed decisions into well informed ones.  However, in so far as the problem is a matter of participants’ disadvantaged status, then improving informed consent procedures would likely fail to suffice.  After all, participation motivated by desperation or a lack of alternative options can only be thought of as voluntary in a formal sense, and access to information isn’t going to be able to change that.

Targeting a Vulnerable Population

In “Ready-to-Recruit” or ‘Ready-to-Consent’ Populations: Informed Consent and the Limits of Subject Autonomy,” Jill Fisher outlines the efforts of pharmaceutical companies and the industry more generally to attract subjects for testing while relying on the concept of informed consent as their ethical justifications. In the industry, informed consent has become the primary criteria for determining whether or not a research study is ethical. It is premised on the assumption that individuals act as autonomous beings who make their own carefully considered decisions about participating in research on the basis of the information given to them. However, Fisher argues that most prospective subjects have already decided to take part in clinical studies before receiving any information that would influence their decisions not to. As a result, the industry takes credit for complying with the well-established ethical requisites, but is really only taking advantage of citizens who are motivated to participate by other factors. She gives three examples of motives that are unrelated to informed consent—intractable disease, lack of health insurance and economic need. Informed consent models hide the broader implications of research, and obscure its own insufficiency as a mechanism to lessen the burden of research on disadvantaged groups.

I think that Fisher has a point when she says that the underlying reasons for participation in clinical trials are clouded when informed consent criteria are over-emphasized. However I think she is also taking on a much larger issue than is possible for her to address. The reason people join trials is never going to be purely altruistic. People join them for some kind of compensation, or in the blind hope that they will relieve suffering, and in doing so take on the associated risks. Depending on how you look at it, one either has an inalienable right to use one’s own body in whatever way one chooses, or one doesn’t. I think Fisher is trying to address the structural and contextual reasons for why people participate, but these reasons go beyond what she is capable of contributing. For example, people do sell themselves to trials because of poverty, but changing this would be to address the issue of poverty itself, which is clearly one of the most difficult problems of humanity. One solution Fisher offers is to place restrictions on participation in trials. However this is invading people’s inalienable right to their body. I think a very legitimate problem arises when companies do not explicitly or honestly disclose the full extent of the risks or potential side-effects of the trial. However, this is in some sense not morally blameworthy because determining side-effects is the very purpose of the trials. It seems like it would be fairly obvious that anyone offering their bodies for untested medical experimentation is going to run the risk of having their health compromised, and to take the risk is at least a minimally autonomous decision, regardless of how much autonomous consent forms are emphasized. Targeting vulnerable populations is also a morally dubious practice; but surely these opportunities for compensation or experimental medicine have greatly benefited desperate people, and I feel like these opportunities should persist. It may be that structural features create incentives to take the risk of participation, but this is not something that can be addressed my medical industry practice. She offers some solutions, such as de-emphasizing informed consent forms, stressing transparency, and creating partnerships between researchers and subjects. These solutions are useful and I think should be adopted in many cases, but they will not change the fact that people will sell their bodies for compensation, and if we want to challenge their right to do that we are challenging the principle of self-ownership.

 

Use of Placebo Arm vs. Standard Treatment for Offshored Clinical Trials

In response to the 1994 AZT controversy in Africa regarding placebo use, a revision to the Helsinki Declaration, which provides guidelines for human biomedical research, stated that placebos should not be used when treatments are known and “a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods.”  CRO researchers and pharmaceutical companies have argued that this new guideline compromises scientific integrity.  However, I believe that the elimination of a placebo arm when known treatments exist is not only more ethical, but also more scientifically useful.

First, comparisons of novel treatments against standard treatments make the results of offshored RCTs more generalizable to populations of the first-world and the upper class in poor countries—important because an overwhelming majority of customers fall into either of these groups.  These patients are not treatment-naive like the populations typically found in third-world countries.  Treatment-naivety refers to populations that have not been previously diagnosed or treated for a particular condition, and considered ideal candidates by pharmaceutical companies.  When a placebo arm uses treatment-naive individuals, the variables affecting the results are minimized.  Statistically, this could improve the result of the RCT which explains why pharmaceutical companies would be interested in finding these candidates.  However, people in developed countries are often on many kinds of medications anyway; therefore, testing against a standard treatment that introduces more variables (e.g. because patient compliance is not guaranteed) gives a better idea of efficacy in the ‘real world’.

The criticism from pharmaceutical companies and CROs against eliminating the placebo arm appears to partially come from an underlying threat of the standard treatment showing better results than the novel treatment that they are investing in; however, their worries can be used to discourage the production of ‘me-too’ drugs.  These drugs usually do not have much scientific value since they are not truly innovative treatments and usually exploit existing knowledge to produce treatments with similar efficacy.  The use of standard treatment can reduce the ‘me-too’ phenomenon because the closer the novel drug is (in terms of mechanism) to the standard, the greater chance of the RCT finding no statistically significant result.  In addition, it encourages pharmaceutical companies to research drugs for diseases that do not currently have effective treatments because this will offer them the best chance of finding a statistically significant positive result, thereby increasing useful medical knowledge.

Unfortunately, companies have found ways to circumvent the new revisions to the Helsinki Declaration by providing the ‘local equivalent’ of the best medicine, which could amount to the same thing as a placebo in very poor areas.  ‘Local standards’ are problematic because they are not generalizable outside of the local area.  Furthermore, it seems unethical to hold back the best existing treatments for patients in their ‘control’ arm when it’s not a huge burden on the companies to provide it.  Therefore, this practice needs to be stopped by having the FDA only approve drugs whose RCTs  include a standard treatment that is recognized in first-world countries (perhaps there should be a list of ‘standards’ acceptable by the FDA), regardless of where the trials have taken place.   By dictating that only studies whose protocols meet the same standards as a study conducted in North America can be given FDA approval regardless of where the study was actually performed, it helps to protect clinical trial participants offshore from participating in unethical trials.

What to do about offshore clinical trials

In Adriana Petryna’s article “Clinical Trials Offshored: On Private Sector Science and Public Health,” she makes a very interesting point about the trial and error relationship of the pharmaceutical industry and the ethical regulations. She points out that it takes a scandal for flaws in the emerging industry to be fixed. Under this view – as tragic as some of the consequences of problems in the pharmaceutical industry can be – they come alongside a newly growing and emerging industry; it is by learning from these mistakes that we can make the industry better. Essentially, mistakes are tragic, but they are necessary for growth and development in the pharmaceutical industry.

Another interesting point Petryna addresses is the idea of who should be held accountable for regulating the offshore clinical trials. As a side note, my favourite part of She makes the point that the FDA claim to regulate the offshore trials but as Petryna points out, this is just not the case. She addresses how ethical review boards should be set up but she brings up the important issue of the cost of the boards. Who should have to pay for these ethical boards? Who should fund them?

As much fun as it is to discuss the problems with clinical trials and think of ways to regulate them, at the end of the day, ethical review boards will cost money and someone needs to front the bill – someone needs to be held accountable for overseeing these trials and someone needs to pay the people for overseeing it. If we make the CROs pay for it, we are left with the problem of conflict of interest. At the same time, however, who else should pay for it? Should the host countries have to pay for it? Or should it be the countries receiving the medication?

The problem with the pharmaceutical industry is that it is an area where science, public health and commerce meet. It’s an area where people are making money off other people’s poor health… corruption and greed is a problem in every industry, but when it comes to people’s health, it seems to be even more unforgivable. These pharmaceutical companies do need to be watched, but unfortunately, in our capitalist North America, things to come down to money so until we can find a way to regulate the pharmaceutical companies and fund it without a conflict of interest, we’re sort of left in this grey area where we have to settle with the trial and error method of regulating things in the pharmaceutical industry.

Asymmetrical Balances of Power

Many of our discussions around medical epistemology surround what is perceived to be asymmetrical balances of power: for instance, we might point to the vast resources available to pharmaceutical industry to shape medical thought or the power imbalance between patients and doctors. Adriana Petryna, in her article “Clinical Trials Off-shored: On Private Sector Science and Public Health” adds yet another power asymmetry to the list: the imbalance between contract research organizations (CROs) and middle and lower-income trial participants in other countries with limited treatment options.

Petryna asserts that CROs direct the course of research in many ways: they might direct the course of what is researched by refusing to bid on contracts that are too costly to run (26), or they can change the inclusion criteria to allow or disallow certain participants (27). Furthermore, they might chose the “most cost-effective tools to observe patients’ symptoms” as opposed to more expensive and comprehensive exams during the research project (35), and sign participants up using “incomplete contracts” which allow for manoeuvrability and exit strategies to remove the drug or change locations after the trial starts (33). Middle- and lower-income trial participants, on the other hand, have less power. With high demand for specialized care but low incomes and little or no government-subsidization (37), they depend on trials for medical care.

With this kind of asymmetrical power structure, there is concern that ethical norms become relative to the region. In particular, the worry is that CROs have the capacity to develop trials within poorer countries that better demonstrate their drugs’ benefits to the comparitive detriment of those enrolled, e.g., by comparing against a placebo as opposed to best standard treatment as might be done in more wealthy countries. There are two arguments we might make on behalf of the CROs. Firstly, it is most often Phase III trials that are multi-centred and take place in other countries like Poland (22). This means the drug has already been tested on 20-80 healthy volunteers during Phase I, and 100-300 subjects with the disease in Phase II (26). Though serious side effects may become apparent in Phase III, the likelihood is much smaller given the significant testing that has already been done. Secondly, even if we take it as our ethical obligation to provide the usual best alternative treatment in lieu of a placebo during clinical trials, the actuality is that, in many of these countries, there is no ‘best alternative treatment’ given the high cost. If this is the case, then it seems unlikely that the pharmaceutical companies are actually harming patients by conducting trials there: either the status quo is maintained with the placebo, or there is some potential in receiving the drug.

This is not to say that conducting clinical trials in these ‘treatment naïve’ areas gives us the most accurate information; merely, I mean to say that it seems that ethical obligations are not being violated by conducting trials for FDA-approval in other countries.

The Ruse of Informed Consent

In the article, “Informed Consent and the Limits of Subject Autonomy”, Jill Fisher reviews the reality of subject autonomy in granting consent in clinical trials. She outlines the principle on which informed consent is based, as “the assumption that individuals act as autonomous beings who make measured decisions about participating in research on the basis of information given to them” (2007; 877). She presents three cases in order to demonstrate that the driving forces for giving consent are often based on other contextual influences in which the information provided is not the major influence. The three cases she presents demonstrate the following motivations for giving consent as: patients seeing clinical trials as granting access to unaffordable health care, a possible option when facing a degenerative disease, and additional income for healthy patients (2007; 885).

Within the contexts of these specific cases, the patients consider these motivations as outweighing the risks presented in informed consent, even when in some cases the risks include death. Where death is explicitly outlined as a possible side effect, she acknowledges that this is typically a deterrent (2007; 885), though not much else is. The contextual environment plays an extremely influential role, which predisposes potential participants in clinical trials to give their consent despite the explicit risks outlined in informed consent forms and formalities. Potential participants are “ready to consent” because they often do not have better alternatives (2007; 877).

I view these participants who give informed consent as coerced and I think Fisher would agree. Explicitly outlining and stating all of the possible adverse affects of a treatment in a trial phase does not provide a reasonable basis for potential subjects to reject becoming participants because not participating isn’t an option. Informed consent seems to be a ruse in the same way transparency in medical journal writing is a ruse. It gives the appearance of full information, which is a good thing, but is not actually doing anything additionally. Stating all of the funding parties involved in creating an ‘informational’ medical document, does not make it so that the readers can see what is not there. Similarly, saying something is a possibility is very different than creating an avenue for avoiding that possibility when it is a dangerous one. It seems as though we accept lies and coercion as long as the system encourages honesty about those lies and coercive techniques and overall presents an ironic tone and an eerie facade.