La ley española de defensa de la competencia

RESEARCH

Many media reports, books, articles, and government documents serve up searing criticisms of the power and influence of the pharmaceutical industry. The industry as a whole stands accused of a sea of injustices and corruptions, including aggressive and deceptive marketing schemes, exploitative uses of research sub-jects, a corrupting influence on universities, a shameful use of lobbying, suppres-sion of vital data, bias and amateurism in the presentation of data, conflicts of interest that bias research investigators, and corruption of the clinical judgment of medical students and practicing physicians.¹

Each of these charges derives from concern about some form of unjust influence exerted by pharmaceutical companies. I cannot here consider the full array of alleged forms of influence. I telescope to one area: the recruitment and enrollment in clinical research of vulnerable human subjects, in particular the economically disadvantaged. I focus on the charge that subjects in clinical trials are exploited by manipulative and unfair payment schemes. I treat three problems. The first is the problem of whether the economically disadvantaged constitute a vulnerable group. I argue that classification as a “group” is a misleading characterization that may cause paternalistic overprotection. The second problem is whether the vulnerable poor are exploited by payments that constitute either an undue influence or an undue industry profit. I argue that such assessments should be made situationally, not categorically. The third problem is whether the poor give

“compromised” or nonvoluntary consents. I argue that this third problem, like

the second, is nuanced but practically manageable, and therefore that pharma-ceutical research involving the poor and vulnerable can be carried out in an ethically responsible manner. Whether the research is so conducted is another matter—an empirical problem beyond the scope of my argument.

Some writers seem to argue that these problems are pseudo-problems in developed countries because the research oversight system for clinical research protects subjects against excessive risk and exploitation while demanding good science and clinical promise. If the system fails, this argument goes, then the system should be repaired, thereby resolving concerns about exploitation.²This approach is understandable and tempting, but overly sanguine. There is no evidence that research oversight systems have a firm grasp on problems of exploitation of the economically disadvantaged, let alone that these problems can safely be dismissed. Moreover, I intend my argument to apply globally, in all contexts of pharmaceutical research, irrespective of a country’s system of oversight. Accordingly, I assume nothing about the adequacy of oversight systems.

VULNERABILITY AND ECONOMIC DISADVANTAGE

Some commentators have maintained that we should not use humans as research subjects under any circumstances; others have said that human research subjects should be volunteers only, not persons induced by rewards to participate. I will assume that neither view is defensible and that, under specifiable conditions, it is permissible to involve humans as research subjects and to pay them for their time and inconvenience. However, I do not presume anything about the involvement of persons who are particularly vulnerable to abuse or exploitation, or anything about levels of acceptable risk. Special protections may be needed for some subjects, and sometimes it is inappropriate to use such subjects at all. There may also be a need for strict control of the level of risk allowed.

I will here consider only economically disadvantaged, decisionally compe-tent persons. Several issues arise: Are these subjects vulnerable to morally objectionable enticement into pharmaceutical research? If so, what renders them vulnerable? Do they lack a mental capacity of resistibility to influence?

Is the worry that their inability to gain access to health care forces them to accept research? Is it that offers of money or health care are made that are too good to be refused? Is there something about the level of risk of harm that renders subjects vulnerable? Answers to these questions are understandably controversial.

Vulnerabilities and Vulnerable Groups

Everyone agrees that ethical research requires impartial review to safeguard the rights and welfare of all subjects and that some research involving vulnerable subjects needs special scrutiny. Less clear is which populations, if any, should be classified as vulnerable to inappropriate influences. Discussion of issues about the vulnerability of research subjects, commonly referred to as “vulnerable groups,”

has primarily focused on embryos, fetuses, prisoners, children, psychiatric patients, the developmentally disabled, those with dementia, and the like. Until recently little attention has been paid to populations of persons who possess the capacity to consent, but whose consent to participation in research might none-theless be compromised, invalid, or unjust. Prisoners have been the paradigm class, but the economically distressed provide a comparable example.

My concern is with persons who are impoverished, may lack significant access to health care, may be homeless, may be malnourished, and yet do have the mental capacity to volunteer in safety and toxicity (phase I) drug studies sponsored by or managed by pharmaceutical companies. They possess the basic competence to reason, deliberate, decide, and consent. Data suggest that somewhere between 50% and 100% of subjects who are healthy volunteers self-report that financial need or financial reward is the primary motive for volunteering.³Persons of this description are certainly involved in some pharmaceutical research in North America, though the extent of their use is not well understood.⁴It is also known that the poor are used in other parts of the world, sometimes in developing countries, but the scope of their use is even less well studied and reported. I will not distinguish between the economic conditions in diverse countries in which research is conducted, but I will distinguish between circumstances in which it is reasonable to expect that basic health care is available to subjects outside of contact with research teams and circumstances in which basic health care is fundamentally unavailable to research subjects.

It is often assumed that the economically disadvantaged are more vulnerable to exploitation by pharmaceutical companies than subjects with stable economic resources.⁵This claim is intuitively attractive, but no data specific to pharmaceu-tical research support it, and some data in nonpharmaceupharmaceu-tical research cast doubt on it.⁶Nonetheless, I will assume its plausibility. What cannot be assumed is that there is a clear connection between economically disadvantaged groups and vulnerability or between vulnerability and exploitation by pharmaceutical companies.

The class of the economically disadvantaged who are vulnerable has sometimes been treated in the literature as narrow, at other times as broad. Those so classified may or may not include individuals living on the streets, low-income persons who are the sole financial support of a large family, persons desperately lacking access

to health care and physicians, and persons whose income falls below a certain threshold level. These individuals could have been in their current situation for many years, but they could also be temporarily unemployed, enduring a family disruption, working through bankruptcy, or fighting a short-term illness.

The notion of a “vulnerable group” has lost much of its historical significance in bioethics and health policy since it was first established in the1970s, because so many groups have been declared vulnerable—from the infirm elderly, to the undereducated, to those with inadequate resources, to pregnant women, to whole countries whose members lack rights or are subject to exploitation.

The language of “vulnerable groups” suggests that all members of a vulnerable group—all prisoners, all poor people, all pregnant women, and the like—are by category vulnerable, and perhaps incompetent to make their own decisions. The problem is that for many groups a label covering all members of the group overprotects, stereotypes, or even disqualifies members who are capable of making their own decisions.⁷ “Vulnerable" is an inappropriate label for any class of persons when some members of the class are not vulnerable. For example, pregnant women as a class are not vulnerable, though some pregnant women are.

Accordingly, I will not speak of the economically disadvantaged—“the poor”—as a categorically vulnerable group, though they have often been so categorized.⁸

However, I will speak of vulnerabilities. As necessary, I will focus on the forms, conditions, and properties of vulnerability. Ideally, research ethics will some day supply a schema of forms and conditions of vulnerability, rather than a list of vulnerable groups. These forms and conditions would be composed of the properties and circumstances that render a person vulnerable as a research sub-ject—for example, incompetence to consent, misunderstanding the objectives of research, increased risk, and socioeconomic deprivation that breaks down one’s resistance to influence attempts.⁹

The Concept of Vulnerability

“Vulnerability” is poorly defined and analyzed in literature on the subject. Many point to incapacities to give an informed consent, whereas others point to unequal relationships of power and resources, such as those between the economically disadvantaged and research sponsors or investigators. The notion of vulnerability in research requires some form of influence either by a second party or by some condition that renders the person susceptible to a harm, loss, or indignity.¹⁰

“Harm” and “loss” are here to be understood in terms of a thwarting, defeating, or setting back of some party’s interests.¹¹ “Harm” is sometimes constructed broadly to include actions that cause discomfort, offense, indignity, or annoyance.

Narrower accounts view harms as setbacks to bodily and mental health. Whether a

broad or a narrow construal is preferable is not a matter I need to decide.

Everyone agrees that significant bodily harms and comparable setbacks to significant nonbodily interests are paradigm instances of harm, and I will restrict myself to these arenas.

The economically disadvantaged are vulnerable in several ways to influences that introduce a significant risk of harm. Their situation leaves them lacking in critical resources and forms of social power, especially access to economic resources and government programs that might be brought to bear on their behalf. They may not be able to resist or refuse acceptance of the risk involved, requiring trade-offs among their interests.¹²What, then, should be done to protect the interests of those who might be abused or exploited in pharmaceutical research?

CATEGORICAL EXCLUSION OF THE ECONOMICALLY DISADVANTAGED A tempting strategy is to exclude economically disadvantaged persons categori-cally, even if they are not categorically vulnerable and even if they meet all conditions for participation in clinical trials. This remedy would eliminate the problem of their unjust exploitation in pharmaceutical research, but it would also deprive subjects of the freedom to choose and would often be economically harmful to them.

Nothing about economically disadvantaged persons justifies such an exclusion, as a group, from participation in pharmaceutical research, just as it does not follow from their status as disadvantaged that they should be excluded from participation in any legal activity. There is an increased risk of taking advantage of the economically distressed, but to exclude them altogether would be an inexcusable form of discrimination. Exclusionary protections of competent, dis-advantaged persons may only serve to further marginalize, deprive, stigmatize, or discriminate against them. Many economically disadvantaged persons believe that participation in research is a worthy and personally satisfying social con-tribution as well as a means to the reduction of their economic plight. To them, research provides an opportunity to earn money in exchange for short-term and unskilled effort, whereas exclusion from participation is an unjust deprivation of liberty and an offensive form of paternalism.

Consider the weakly analogous case of prisoners, who have long been the paradigm of competent persons who are categorically excluded from phase I clinical trials. The right to volunteer as a research subject is denied to prisoners in U.S. federal policy on grounds of the potential for manipulation or coercion in penal institutions. Were this same potential to exist for economically disadvan-taged persons, the same categorical exclusion might be appropriate. However, this

problem needs to be examined in each context to see if persons who have the capacity to give an informed consent are nonetheless not able to consent freely in that context.

Assume, for the moment, both that we can obtain consents that are adequately informed and voluntary and that the research is welcomed by subjects as a source of income and possibly also as a source of contact with health care authorities.

Under these conditions, a subject’s situation of economic disadvantage is irrele-vant. These subjects will be more advantaged by research participation than would other potential subjects, because the money earned and the access to health authorities will be more significant to them. To exclude voluntary subjects from participation would doubly disadvantage them, depriving them of money in their already economically disadvantaged circumstance.

PAYMENT AS INDUCEMENT: PROBLEMS OF UNDUE INFLUENCE AND UNDUE PROFIT

Payments and rewards such as free health care offered to potential pharmaceutical research subjects present issues about the acceptability of inducements in exchange for services. Problems of voluntariness are prominent.

Voluntariness and Types of Influence

A person acts voluntarily if he or she wills an action without being under the controlling influence of another person or condition. Of course not all influences are controlling, and not all controlling influences are unwarranted. What, then, are we to say about payments to potential subjects? Are they controlling? Are they warranted?

Three categories of influence need to be distinguished: persuasion, manipula-tion, and coercion.¹³ In persuasion, a person believes in something through the merit of reasons another person advances. This is the paradigm of an influence that is not controlling and that is warranted. Manipulation, by contrast, involves getting people to do what the manipulator wants through a means other than coercion or persuasion. In recruitment for clinical studies, the most likely forms of manipulation are (1) informational manipulation that nonpersuasively alters a person’s understanding and (2) offers of rewards. Critics of pharmaceutical company recruiting practices have accused companies of informational manip-ulation through withholding critical information and through misleading exag-geration. Other critics have said that offers of money and health care are excessively attractive. Finally, coercion occurs if and only if one person either

intentionally and physically compels another or intentionally uses a credible and severe threat of harm or force to control another.¹⁴ Some threats will coerce virtually all persons, whereas others will coerce only a few persons. Coercion itself is probably rare in the setting of clinical research, but a sense of being left without any significant alternatives other than acceptance of an offer that one would prefer to decline may not be uncommon. I turn now to that problem.

Constraining Situations

Subjects do sometimes report feeling heavily pressured to enroll in clinical trials, even though their enrollment is classified as voluntary.¹⁵These individuals may be in desperate need of some form of medication or research may be a vital source of income. Attractive offers such as free medication, in-clinic housing, and money can leave a person with a sense of having no meaningful choice but to accept research participation. Influences that many individuals easily resist are felt by these potential subjects as constraining them to a particular choice.

In these constraining situations—sometimes misleadingly called coercive situa-tions—there is no coercion, strictly speaking, because no one has physically compelled another or intentionally issued a threat in order to gain compliance.

A person feels controlled by the constraints of a situation such as severe illness or lack of food and shelter, rather than by the design or threat of another person.

Sometimes people unintentionally make other persons feel “threatened” by their actions, and sometimes illness, powerlessness, and lack of resources are perceived as threats of harm that a person feels compelled to prevent. No doubt these situations are significant constraints on choice, though not ones that involve compulsion or threats.

The prospect of another night on the streets or another day without food could constrain a person to accept an offer of shelter and payment, just as such conditions could constrain a person to accept a job cleaning up hazardous chemicals or sewers that the person would otherwise not accept. The psycholo-gical effect on persons forced to choose may be similar, and a person can appropriately say in both cases, “I had no choice; it was unthinkable to refuse the offer.”

PAYMENT, UNDUE INFLUENCE, AND UNDUE PROFIT

In constraining situations, monetary payments and related offers such as shelter or food give rise to questions of undue influence on the one hand and undue profit on the other. The “Common Rule” in the United States requires investigators to

“minimize the possibility of” coercion and undue inducement, but it does not define, analyze, or explain these notions.¹⁶Issues of exploitation, undue induce-ment, and undue profit are inadequately handled in the bioethics literature as well.

Monetary payments seem unproblematic if the payments are welcome offers that persons do not want to refuse and the risks are at the level of everyday activities. Becoming a research subject, under these conditions, seems no different than accepting a job offer or agreeing to a contract that, without payment, one would not accept. Indeed, the offer of research involvement is an offer of a job or contract in which mutual benefit can and should occur (setting aside questions of sanitary conditions, impartial committee review and approval, and the like).¹⁷ However, inducements become increasingly problematic (1) as risks are increased, (2) as more attractive inducements are offered, and (3) as the subject’s economic disadvantage is exacerbated. These are the three principal conditions to be considered in assessing whether exploitation occurs.¹⁸

The heart of the problem of exploitation is that subjects are situationally disadvantaged and without viable alternatives, feel forced or compelled to accept attractive offers that they otherwise would not accept, and assume increased risk in their lives. As these conditions are mitigated, the problem of exploitation diminishes and may vanish; but as these conditions are heightened, the potential for exploitation increases.

As this formulation suggests, the condition of an irresistibly attractive offer is a necessary condition of “undue inducement,” but this condition is not by itself sufficient to make an inducement undue. There must also be a risk of harm of sufficient seriousness that the person’s welfare interest is negatively affected by assuming it, and it must be a risk the person would not ordinarily assume.¹⁹I will not try to pinpoint a precise threshold of risk, but it would have to be above the level of such common job risks as those of unskilled construction work.

Inducements are not undue, then, unless they are both above the level of standard risk (hence “excessive” in risk) and irresistibly attractive (hence “excessive” in payment) in light of a constraining situation. Although these offers are not coercive, because no threat of excessive risk or of taking money away from the person is involved, the offer can be manipulative. Indeed, since irresistibly attractive payment is involved, these offers almost certainly should be categorized

Inducements are not undue, then, unless they are both above the level of standard risk (hence “excessive” in risk) and irresistibly attractive (hence “excessive” in payment) in light of a constraining situation. Although these offers are not coercive, because no threat of excessive risk or of taking money away from the person is involved, the offer can be manipulative. Indeed, since irresistibly attractive payment is involved, these offers almost certainly should be categorized