Addressing Vulnerability Within Clinical Research: How Do We Do It?

The issue of vulnerability as an ethical question in research is one that many acknowledge but few know how to address. The gap in our understanding of this topic has raised questions on how to address the issue of vulnerability and how to protect populations who are considered vulnerable based on various social, economic, medical, and cultural stressors. One of the primary factors contributing to this dilemma is the lack of comprehensive and effective guidelines for identifying and then protecting these populations. This essay will analyze and defend the definition of vulnerability put forth by Samia A. Hurst in her essay “Vulnerability in Research and Health Care; Describing the Elephant in the Room?” in the context of other ethical values and scenarios.

Background

There are a number of international guidelines for research ethics that address the protection of vulnerable groups, including the Belmont Report (1976), the Declaration of Helsinki (1964), and the 45 Code of Federal Regulations 46 (1981) (Hurst). However, a consistent problem has been how to define what a vulnerable population is, with these definitions varying from broad to specific. This is an issue Samia Hurst directly addresses and intends to remedy in her essay “Vulnerability in Research and Health Care; Describing the Elephant in the Room?” (Hurst). A standard definition for ‘vulnerable populations’ is those who are “susceptible to coercion or undue influence”, according to the Code of Federal Regulations (CFR). Hurst suggests that it is generally accepted that the vulnerable should be afforded special attention or protection, but defining what constitutes a vulnerability is more difficult (Hurst).

Perhaps at the basis of our conceptions of exploitation in bioethics is the Mere Means Principle put forth by Immanuel Kant in “The Groundwork of the Metaphysics of Morals”. According to this Principle and the Formula of Humanity, it is morally wrong for humanity to treat people merely as a means to an end, rather than as ends in themselves (Kerstein). When one treats another as merely a means to an end, an unfair exchange has occurred because one has benefited from the disadvantage of another. Our definitions of exploitation in clinical research appear to be shaped around the idea of being “used” or “taken advantage of”, suggesting that the two concepts are deeply intertwined (Wertheimer).

One particular ethicist, Hans Jonas, has considered the Kant’s Mere Means Principle as a moral driving force behind opposing all research involving humans, except for in dire emergency situations such as with epidemics (Jonas). Jonas argues that because research is focused more so on generating knowledge for a social good, then the use of human subjects in order to reach this end violates the Mere Means Principle (Jonas). Furthermore, the recruitment of volunteers for clinical research is unethical because it considers social good over the good of the individual (Jonas). The primary issue with Jonas’s argument is his insistence that research using human subjects is ethically wrong unless there is a demonstrable emergency need for it. How many people must become sick, suffer, or die before something is considered an epidemic? Would this not be equally as unethical? Ultimately what Jonas’s argument does is highlight a practical problem with the Mere Means Principle, which has guided research ethics for most of its history. When is a situation acceptable, let alone ethical, and when is it not?

Alan Wertheimer writes that the concept of “exploitation” is often entangled with research involving vulnerable populations in his book “Rethinking the Ethics of Clinical Research: Widening the Lens” (Wertheimer). Ruth Macklin defines exploitation as “occurring when wealthy or powerful individuals or agencies take advantage of the poverty, powerlessness, or dependency of others by using the latter to serve their own ends without adequate compensating benefits for the less powerful or disadvantaged individuals or groups” (Macklin). In the fifth chapter of Wertheimer’s book, which is dedicated primarily to understanding exploitation in clinical research, Wertheimer interrogates the notion that exploitation is always wrongful, even saying that it can be mutually beneficial (Wertheimer). The concept that drives Wertheimer’s conception of exploitation, whether wrongful or mutually advantageous, is that of autonomy. Through a number of hypothetical examples, he demonstrates that some cases, like that of the Nazi doctor performing experiments on people in death camps, constitute wrongful exploitation, while others, like that of a lumber retailer who raises his prices when the demand for lumber goes up after a hurricane, does not necessarily do so (Wertheimer). In the first case, the people on whom the experiments are being performed were not able to consent to the experimentation and were then, as a result, exploited. However, in the case of the lumber retailer, the customer must consent to pay the higher price in order to receive the lumber and rebuild their home. While it might be inconvenient for the customer to have to pay this price, he is still benefiting from this exchange by receiving lumber, though this exchange would still be considered exploitation, not wrongful exploitation.

Just as Wertheimer identifies certain situations in which exploitation might be considered mutually beneficial, other philosophers have done the same with Kant’s Mere Means Principle, which allows no exceptions (Kerstein). Though it might be commonly accepted in severe cases that the Mere Means Principle applies, more day-to-day situations become difficult to navigate, according to Samuel Kerstein in his essay “Treating Others Merely as Means” (Kerstein). Kerstein provides two situations, one in which a man murders an innocent person in order to prevent a nuclear explosion, and one in which a tennis player tries to defeat his opponent in a tournament in order to advance to first place (Kerstein). The first case, which is very much less ordinary, is generally accepted as an example of the Mere Means Principle and the questions it raises. However, the second case presents an issue similar to that of the lumber retailer. While the situation logically follows what Kant defines as treating another person as a means to an end, it seems neither sound nor practical to say that in an athletic competition the winner violates Kant’s Mere Means Principle. This is where Hurst’s concerns about vulnerability and exploitation come into play. While it might be accepted that the vulnerable should be protected in research, our definition of who is vulnerable relies more so on identifying potential vulnerabilities amongst a multitude of possibilities rather than on defining what kinds of wrongs these populations might incur in the process of participating in research (Hurst). In this essay, I will use the framework put forth by Kant’s Mere Means Principle and Wertheimer’s conceptions of exploitation in order to defend Hurst’s methodology for defining vulnerability and protecting these populations.

Defining Vulnerability According to Hurst

In her essay “Vulnerability in Research and Health Care; Describing the Elephant in the Room?”, Samia Hurst questions our current methodology for defining vulnerability in research (Hurst). She begins her argument by assessing consent-based approaches, ultimately finding that consent is a necessary condition for protecting subjects, but it is not a sufficient condition for defining a vulnerable population (Hurst). Though there are certain situations in which it is acceptable to say that someone who cannot voluntarily consent to participation can be defined as vulnerable, such as with patients who are terminally ill or with children, there are other cases, like with pregnant women or economically disadvantaged peoples, where participants are freely capable of consenting but still might be at risk of being wronged (Hurst). Hurst then considers a variant of consent-based approaches that involves including limits on the ability to avoid exploitation or harm in the definition (Hurst). She highlights that these approaches can similarly be too broad or too specific (Hurst). Furthermore, if we root our definition of vulnerability in consent but include susceptibility to exploitation or harm, our definition will still be insufficient (Hurst). Ultimately, Hurst concludes that defining a vulnerable population as one who is likely to be exploited or incur additional harm is not comprehensive enough because what these people risk is being “wronged” rather than harmed (Hurst). Considering more comprehensive definitions, Hurst finds a similar issue. Though these definitions, which rely on both consent and fairness, are based in equity and freedom, they still do not sufficiently cover all of the possibilities (Hurst).

It is at this point that Hurst introduces a new framework for identifying and protecting vulnerable populations. Instead of relying heavily on trying to identify every type of vulnerability and craft a definition that covers all of these, we should turn our focus more towards considering what kinds of potential wrongs are present within a certain context or study design and then identify who is more susceptible to incurring these wrongs (Hurst). Hurst defines that vulnerability as a claim to special protection is “an identifiably increased likelihood of incurring additional or greater wrong” (Hurst). Her focus on wrongs, which can include both removal of access to something to which someone has a valid claim and wrongful harm, allows a more nuanced and specific approach to identifying and protecting vulnerable populations (Hurst). Hurst does identify that this definition lacks a clear cut-off line between defining vulnerable and non-vulnerable populations and counters that in situations where certain people or groups are identifiably more likely to incur wrongs, this framework should be sufficient (Hurst). She concludes her main argument by asserting that merely defining vulnerability does not identify those who have a share in the duty of protecting these people and that the responsibility will vary based on the scenario (Hurst).

Application and Defense of Hurst’s Definition

Hurst outlines a series of questions that researchers can apply to their research in order to determine which individuals or groups might be susceptible to being wronged (Hurst). The questions are as follows: 1) Is there an identifiable potential wrong? 2) If yes, are some people identifiably more likely than others to incur this wrong, or likely to incur it to a greater degree? 3) Who shares in the duty to minimize, or avoid, this wrong, and does it include us in any way? 4) What should we do to minimize this increased likelihood or degree, or to compensate for it in ethically justifiable ways? (Hurst).

The Surfaxin Trial, highlighted by Alan Wertheimer, is a historical situation that might have been improved had it been assessed using the questions outlined by Hurst. In the Surfaxin Trial, a private U.S. drug company tested the efficacy of a respiratory surfactant (Surfaxin) in Bolivia and other areas of South America despite acknowledging that the drug would only primarily be available in the U.S. and Europe because of its high cost (Wertheimer). The study was designed as a multi-centered, double-blinded, randomized, two-arm placebo controlled trial involving 650 premature infants with Respiratory Distress Syndrome (RDS), the disease for which the drug is designed (Wertheimer). The treatment group would be given Surfaxin as an intervention, while the control group would be given “sham air” without any drug (Wertheimer). It should be noted, however, that the “sham air” treatment had already at this point been shown to improve survival and was superior to the most common treatment available in Bolivia and that infants in the control group would not be denied any superior treatment readily available in Bolivia if their proxy were to request it (Wertheimer).

While there are a number of ethical issues present in this case, the primary one that will be discussed is the placement of the trial in a Less Developed Country (LDC) rather than with the target population. Using the criteria for a vulnerable population as outlined in the Belmont Report (racial minorities, the economically disadvantaged, the very sick, and the institutionalized), we see that this population falls under the scope (Hurst). However, the Belmont Report does not explicitly identify children as a vulnerable population, though this is often the group that many feel need protection in clinical research. Not only are these infants located in an LDC, and therefore economically disadvantaged, but they are also not capable of autonomy, and thereby consent. Though their parents were able to give proxy consent, and though these infants would likely have benefitted in some way from the trial, whether from the treatment or the control intervention, this scenario still raises the question of whether its effects qualify at the least as a wrong and at the worst as a wrongful harm.

Applying the framework Hurst outlines, a potential wrong that can be identified is that this treatment would likely not be available on any kind of widespread basis in Bolivia, and though the infants who were included in the trial and were randomly selected to be part of the treatment group, as well as the infants in the control group who received the “sham air”, likely benefited in some way from the trial, the question must be raised of whether their individual benefit warrants the level of risk and likelihood of being wronged which the study design allows. Furthermore, we must ask whether each infant’s individual benefit outweighs the drug company’s seemingly intentional and financially driven decision to place this trial in an LDC. Is there any kind of collective social benefit for the country itself that arises for from the placement of this trial in Bolivia? Perhaps if Surfaxin were intended to be readily available within the nation rather than only for the infants who participate in trial there would be some social benefit, but this is not the case in this scenario.

According to the Mere Means Principle, this case could be considered exploitative because the infants included in the trial would be taken advantage of for their country’s lower economic power in order to meet the needs of high income nations. Wertheimer argues that because there is some benefit for the participants in this trial it falls under his criteria for a mutually-advantageous exploitation (Wertheimer). Furthermore, he argues that withholding a potentially efficacious treatment option from infants who might otherwise die based on our notions of exploitation might in itself be considered exploitation (Wertheimer). However, the real question present is not so much that this study design is entirely exploitative, but rather that it fails to establish a reasonable social benefit for the context in which it is placed. If one of the primary principles of clinical research is to generate scientific knowledge for the benefit of society, then we must consider if only certain subsets of society as a whole will benefit over others. It would be naive to expect that all clinical research and resulting interventions can be made widespread for all of society considering potential economic and social constraints, but within this scenario, the benefit would be primarily for Developed Nations rather than the context in which it was placed. Perhaps the benefit for the participants would be significant, but does this individual benefit warrant out-sourcing the potential burdens to already disadvantaged peoples?

Something to consider is how this flawed study design might have been remedied if it had included more comprehensive protection of or compensation for this vulnerable population. Research involving vulnerable populations is not in itself exploitative, but it must include special protections for these populations. If the trial had been placed within the United States or Europe, where Surfaxin was intended to be marketed, then the participants would have the added benefit of directly contributing to a measurable social good. By placing this trial in a LDC without making efforts to make Surfaxin readily available to the Bolivian population, the drug company withheld this benefit from the population and instead placed greater importance on their own financial gain. By placing this trial within this social context, the researchers created a viable claim for widespread access to this treatment but failed to address this claim, as they are obligated to do. The participants of this trial would also have been placed at a greater risk than potential participants in higher income countries because of their limited access to healthcare in the event that the intervention was proven to be ineffective or even harmful. The potential individual benefit from participating in this trial is not sufficient in offsetting the increased risk of being wronged and even wrongfully harmed in this case.

Hurst highlights that part of effectively applying her definition of a vulnerable population is determining whose duty it is to minimize or avoid this wrong (Hurst). Often, it is the responsibility of researchers, IRBs, and drug companies, as is the case here. The most obvious protection that could be offered in this case would be an effort by the drug company to offer Surfaxin to the population at a decreased cost. Another option would be to provide resources to the communities being studied in order to help increase access to effective healthcare. While these options may not always be financially plausible in many cases, they are necessary for maintaining the ethical integrity of the study. Without these added benefits and/or protections, the risk of being wronged is too great for the study to be approved. We also see in this case how commonly accepted definitions of vulnerable populations have failed to be comprehensive enough. The population recruited for the study is defined as being economically disadvantaged, which is covered by the guidelines in the Belmont Report, as previously stated. Furthermore, the researchers were able to obtain proxy consent from parents for the study, which means that for most intents and purposes the issue of consent was dealt with. The primary factor that was overlooked in this case was the degree of risk of being wronged. The compensatory efforts made by the drug company did not effectively address this issue, and as a result, the benefits and protections offered were not sufficient.

Moving Forward

Having used Kant’s Mere Means Principle and Wertheimer’s take on exploitation in clinical research to interrogate Hurt’s definition of vulnerability, we reach a crucial question. If it is necessary to protect vulnerable populations in research, sometimes at great financial cost, then what would stop researchers from simply not including these populations in their research? This question is one that commonly arises when the concept of vulnerability is considered and must be addressed in regards to ethical codes already established. The Belmont Report, written in 1976, considers this response through three principles: respect for persons, beneficence, and justice (Belmont). Indeed, many of the ethical reasons regarding the protection of vulnerable populations outlined in this paper are derived from these principles. The first of the three, respect for persons, addresses the individual right to autonomy and is concerned primarily with informed consent, the cornerstone of research ethics (Belmont). The second, beneficence, focuses more on the concept of “do no harm”, and its concern lies in a reasonable and fair assessment of risks and benefits. As outlined in the previous section, the risk and benefit ratio is one that can make or break the ethical validity of a study and is what Samia Hurst spends most of her essay investigating (Belmont, Hurst). One of the defining factors of the principle of beneficence is its focus on the responsibility of researchers to minimize potential risks while also maximizing benefits (Belmont). With this in mind, we move on to the last principle: justice. This principle is the one most directly related to the obligation researchers have to equitably distribute the costs and burdens of their research, while also making sure to address the issues commonly faced by vulnerable populations (Belmont). Using both the principle of beneficence and the principle of justice in tandem, we must come to the conclusion that researchers must equally consider the needs, both social and medical, of vulnerable populations. Citing financial burdens as a way of neglecting the concerns of these populations would be equally as unethical as failing to protect them from wrongdoing. This concept that researchers can selectively exclude certain individuals or groups from research simply because it would be too inconvenient to accommodate their needs or to protect them is clearly in conflict with the principles of the Belmont Report and represents a failure to understand one of the primary principles behind research: to generate knowledge for social good.

Researchers have an obligation to equitably include vulnerable populations in their research while also considering any increased likelihood of exploiting these populations. The issue that appears to have been in the most need of being addressed was that of how to define a vulnerable population, as Hurst asserts. And in order to defend the notion of special protections, it is necessary to consider the ethical rights that all people have when participating in research and to consider how these rights might be violated or infringed upon from individual to individual and population to population. The Mere Means Principle provides the framework that has shaped the history of bioethics for many years, but when placed in conversation with Wertheimer’s ideas about exploitation and when we consider how many ways it can be interpreted, it is necessary to highlight when the possibility of being wronged becomes unacceptable.

Bibliography

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