The Inclusion Of Children In Non-therapeutic Medical Research

A Role For Double Effect Reasoning In The Moral Justification Of Pediatric Experimentation

Peter A. DePergola II

ABSTRACT

Abstract

Since Henry Beecher’s 1966 revelation of the scandal at the Willowbrook School, the ethics of biomedical research involving pediatric subjects has never been the same. Throughout history, that conversation has moved from access to protection only to return to access once more. The clear and fruitful debate between Paul Ramsey and Richard McCormick in the 1970s was a forceful step toward punctuating that conversation. Today, we require a vision still more careful and rational, combining the best of prudent restriction and sensible permission to combat issues surroundingthe moral licitness of proxy consent to experimentation, the qualification of pediatric assent to participation in research, and the quantification of risks and benefits in the clinical context. To that end, this essay positsthe argument that there indeed exists a role, in certain cases, for double effect reasoning as a method by which to justify non-therapeutic pediatric research. Double effect reasoning in the research context may lend insightinto the benefits of fostering within the moral philosophical tradition a refined understanding of what constitutes as morally normative for children in the experimentation situation.

I. Introduction

Bioethical debates over the inclusion of children in non-therapeutic medical research are often preceded by the actual events that stimulate them. When reported, however, the implications of such events are typically distorted out of context regarding how and when it may be morally permissible to include children in experimentation. Rational analysis is inevitably forced to the background while the astonishing abuses assume front row [1]. Prima facie, abuses frequently spark the emotional response that most, if not all, related research must be prohibited. The argument usually takes some manifestation of this form: Children are unable to consent, and thus fully understand theimplications of the risks (and lack of benefits) involvedin sacrificing themselves for the “greater good”; therefore, experimentation on those who cannot consent to it, especially if it is non-therapeutic in nature, should be morally prohibited.

In the latter half the twentieth century, one landmark abuse, exposed by Henry Beecher, took command of the debate over how to justify the inclusion of children in medical research. The scandal concerned the hepatitis experiments at the Willowbrook State School. [2] Some seven years earlier, Beecher contended that“there is no justification . . . for risking an injury to an individual for the possible benefit to other people.. . . The individual must not be subordinated to the community. The community exists for man.” [3] Beecher’s response to the research conducted at the Willowbrook School sparked a decade-long debate over the moral licitness of the research strategies applied in the study [4] Saul Krugman, the study’s primary investigator, found his means and intentionsbeneficent. Since all children at Willowbrook wouldeventually contract hepatitis within the institution, a controlled study producing an effective vaccinewould, in the end, prove of direct benefit to thoseexperimented upon.

Retrospective elation, however, does not de facto solve moral problems. [1] Beecher would go on to argue— deontologically—on behalf of the intrinsic rightnessof actions in themselves: “An experiment is ethical or not at its inception; it does not become ethical posthoc—ends do not justify the means.” [5] The differences in moral philosophy between Beecher and Krugman underscore the nature of the paradox that concerns us here: how to improve pediatric medical care by studying the course of disease for the purpose of warding off morbidity in the effort to promote health and well-being while simultaneously protecting the fragile moral status of inevitably vulnerable children. [6] The question is thus raised over whether children, as persons incapable of giving consent, should ever be involved in biomedical research, particularly when the research is non-therapeutic in nature. In the middle and latter half of the 1970s, this question was explicitly addressed in an eminently rational debate between two bioethicists, Princeton’s Paul Ramsey and Georgetown’s Richard McCormick.

That debate, and the need for a nuanced justificationof pediatric experimentation, frames the nucleus of this essay, which moves in six parts. First, it will address the nature of pediatric research. Here, I will cite the history, in a broad and incomplete sweep, of pediatric research to date, along with its movements from access to protection and from protection back to access. Second, it will address the nature of non-therapeutic research with children. Here, I will underscore the terms and conditions elemental to pediatric experimentation, along with the ethical revisions it would do well to assimilate. Third, it will address informed consent as a particular moral issue of primary significance in the debate. Here, I will touch upon the ethics of proxy consent, along with the notions of pediatric assent and dissent.

Fourth, it will synopsize the argument put forth by Paul Ramsey against pediatric experimentation. Here, I will emphasize the concept of the human person as end, along with the ethics of protection over progress inherent to his argument. Fifth, it will synopsize the argument put forth by Richard McCormick in favor of pediatric experimentation. Here, I will accent the concept of natural law, along with the ethics of “ought” as presumed consent inherent to his argument. Sixth, itwill propose a corrective vision and moral justificationof pediatric experimentation. Here, I will utilize the theoretical conception of the principle of double effect, along with its fourfold conditions as applied to pediatric experimentation, to make the argument. Finally, this essay will conclude by having successfully posited the argument that there indeed exists a role, in certain cases, for double effect reasoning as a method by which to justify non-therapeutic pediatric research.

II. Pediatric Research

The modern history of medical experimentation in the United Stated begins undoubtedly with Henry Beecher’s 1966 New England Journal of Medicinearticle “Ethics and Clinical Research.” [7,8] Prior to 1966, children were experimented upon by virtue of convenience. Researchers would often select their own children, servants, or slaves to serve as subjects. Children were also recruited from outside institutions, and came “cheaply,” as it were, because they were viewed as expendable, commodious, and lacking essential value. Hence, in the century prior to 1966, the role of children in medical research can aptly be described as one of explicit child abuse. Beecher’s expressed concerns led to the subsequent introduction of additional regulations by the 1970s, when still more regulations were developed to assist in protecting the vulnerable state of children in medical research. These last safeguards were designed with the intention of completely casting out the inclusion of children in medical research. [9]

Four of Beecher’s twenty-two published cases in 1966 involved gross abuses in children. [10,11,12,13] In 1970, he would publish Research and the Individual,a further comprehensive and systematic critique of the research practices at the time [917]—a critiquethat called, as he wrote, for a “pressing need for a philosopher’s approach, but only by one so wise that he can competently resolve the enormous complexities of the problems involved.” [14] Such an approach would be provided by theological ethicist Paul Ramsey. In the same year, Ramsey published an account of his take on the ethical problems facing biomedicine. [917] Noting that the task of ethics in medicine “is to reconcile the welfare of the individual with the welfare of humankind,” since “both must be served,” [15] Ramsey’s research took on a life of its own. [16] Ramsey’s position, as we will see, was heavily grounded in the necessity of consent as a safeguard by which moral licitness would be achieved in biomedical interventions. [17]

In 1974, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research was established to examine contemporary issues surrounding the protection of human subjects in research. [919] The Commission, noting Ramsey’s position, invoked the philosophical positions of others, most notably moral theologian Richard McCormick, to refute it. That debate will be addressed in depth at a later point. McCormick, as we will see, would take a natural law approach to combat his friend and fellow scholar, arguing in essence that, in the pediatric context, parental consent on behalf of children involved in medical research “is morally valid precisely insofar as it is a reasonable presumption of the child’s wishes,” [18] because there are “certainidentifiable values that we ought to support, attempt to realize, and never directly suppress because theyare definitive of our flourishing and well-being.” [1812]

The National Commission would produce over twenty reports in the 1970s, relying heavily on theBelmont Report for support. Based on the National Commission’s report a year earlier regarding research involving children, the Department of Health, Education, and Welfare would, in 1978 and 1979, propose regulations for pediatric research, thedetails of which would eventually be finalized in theearly 1980s by the Department of Health and Human Services. Although in favor of pediatric research, the Commission noted the vulnerability of children, arising out of their immaturity and dependence, and this notion called for strict criteria to guide the research. Minimally, they were six fold [19]. Depending on the level and prospective risk of harm, additional criteria were added. By the early 1990s, however, the move from access to protection began to shift, albeit slightly, back to access with the support of multiple government agencies. [923-24]

The return to access was the result of at least two factors: (i) the concern that children were being prescribed drugs that had never been tested on pediatric populations, and (ii) the response of the Food and Drug Administration (FDA) to the “politicization,” as Lainie Friedman Ross calls it, “of drug testing and approval by AIDS activists.” [924] In June 1996, the American Academy of Pediatrics and National Institute of Child Health and Human Development hosted a conference regarding the inclusion of children in clinical research. It brought to light that more than eighty percent of medication prescribed to children had never been tested on pediatric populations. By April 1999, the FDA-enforced Pediatric Rule mandated that new drugs be the product of adequately conducted pediatric studies. Because of the eventual success enjoyed by the Food and Drug Administration Modernization Act, passed by Congress in 1997, the Rule was never enforced. By January 2002, the Act wasextended for five years. In March 2004, the Instituteof Medicine, charged with the task of providing further ethical guidance on the matter of pediatric research by the Best Pharmaceuticals for Children Act of 2002, released its report. In short, it noted that in several cases, ethical standards unavoidably serve as impediments to otherwise desirable and useful research. [924-27]

III. Non-therapeutic Research with Children

Non-therapeutic research studies are Phase I clinicaltrials that do not offer the prospect of direct benefitto the subject involved. [20] If the trial foreseesdirect benefit, then the research is permitted on the conditions that (i) the risk is justified by the relationship it shares with the weighed (prospective) benefits, and(ii) the relationship is proportional (i.e., favorable) to the available medical alternatives to which participatory subjects are availed. If, however, the research doesnot offer the prospect of direct benefit (i.e., is non-therapeutic), then the research is permitted on the conditions that (i) the risks are minimal at most; (ii) the transcendence of minimal risk is minor, such that the study is (a) likely to produce knowledge that can be generalized concerning the subject’s condition, or (b) exposes the subject to medical, social, psychological, or educational environments that would ordinarily be tolerated or expected; or (iii) the research is nototherwise justifiable but provides an opportunity tounderstand, prevent, or eliminate serious biomedical problems affecting the well-being of the subject (and similar subjects) and is approved by a committee convened on behalf of the Department of Health and Human Services. [9104]

The primary moral concern for those who advocate careful access rather than stringent protection is whether the study in question is absolutely necessary or even desirable. As Priscilla Alderson and Virginia Morrow note, “‘harm’ is [so] often invisible and elusive, complicated by different estimations . . . [and] viewpoints . . . that the need . . . for ethical controls seems obvious.” [21] Since the safety and efficacy ofnew drugs are at times not established in pediatric populations, phase I and II research prove necessary yet remain above the threshold of minimal risk for subjects. To approve such research, the Institutional Review Board (IRB) must deem the risk in phase Itrials justifiable on the condition that it seems likely to promise direct benefit. However, this is morallyproblematic for at least three reasons. First, this claimflies in the face of the notion that research does not intend to provide benefit. Second, it overstates the potential for a directly beneficial result. Third and finally, it allows parental consent to override pediatric dissent. [9109-10]

Since non-therapeutic research focuses on aspirational,not direct, benefits, several considerations must betaken into account before proceeding with pediatricexperimentation. The first is an adequate sense of risk, cost, harm, and benefit.“Calculating” risks and benefitscan be, as noted above, highly subjective; therefore,the assignment of clear definitions is essential. [22]  Second, one must determine the probability of each— the direct and indirect benefits and risks. Ascertainingthe level of severity is also vital to determining the moral permissibility of foreseen risks involved in non- therapeutic research. [23] Third, the “general welfare” of child subjects also necessitates thorough revision. Because the literature concerning the abuse of children in medical research often contrasts the right of children to be protected with their simultaneous right to be included in valuable research, pediatric research and researchers are often deterred, and children are usurped of their right to be heard through it. [2123-30] Fourth and finally, the notion of intent must be taken into account. If researchers’ intentions are relevant, then phase I studies would be permitted on grounds that they offer direct therapeutic benefit even while the particular trial lacks therapeutic intent. [24]

IV. Informed Consent

Informed consent is the centerpiece of contemporary bioethics [25], and it has served as its backbone since the Beecher exposé. The first principle of the 1946 Nuremberg Code [987], its primary moral purpose is to protect human persons from being abused, and the primary justification for seeking it within the research context are for autonomic and welfarist reasons. [26] Despite its rich history, proxy consent remained unaddressed until the 1964 Declaration of Helsinki, and it lacked finalization until 1983. Contemporarily, most research involving children requires proxy consent. Spelled out in the Common Rule of the federal regulations for the protection of human subjects are the guidelines by which parents are able to provide consent. If the research is therapeutic in nature, the IRB allows consent by one parent; if, however, the research is non-therapeutic (and is above the threshold of minimal risk), the Common Rule demands consent by both parents. These regulations also require ample effort is made to obtain the pediatric subject’s assent to the research–a positive complicity to participate, and not simply the failure to object to participation in experimentation. [987-88]

Proxy consent in the research context is both complex and complicated. [27] The justification of proxy consent is that it is given with the intention of protecting and preserving the best interests of the pediatric subject. Some modern philosophers, such as Ross, contend that proxy consent can be justified on the basis that parent shave a right to raise their children according to their own system of values, and indeed have a legitimate moral interest in doing so. Parental authority has also been invoked to defend proxy consent in that parents, as heads of idiosyncratic families, enjoy the free right to decide what will become of its incompetent members. In these modern contentions, the logic is found in the dual effort to serve the subject and the parents, rather than the subject alone. [988-89]

The notions of pediatric assent and dissent are no less complex and complicated. Unlike proxy consent, which is respected to the degree that it attempts to protect the child, assent is by nature preferential; that is, it is expressive of a positive agreement to be the means by which another’s needs are served. It is helpful to understand pediatric assent as complimentary to both the respect due to the child’s current choices as well as the respect due to the kindof person—morally—the childis becoming. Understood this way, it is reasonable for parents to suspend a child’s immediate autonomy (i.e., current choices) in order to preserve and promote the autonomy to be sustained over a lifetime. [2195] At present, a child’s dissent to participation in research can never be overridden by proxy consent. Respecting pediatric dissent protects children against the perception of parents. Hence, the virtue of the assent/dissent clause ensures that the child is treated with respect and dignity. [2196-98]

V. The Argument Against Pediatric Experimentation: Paul Ramsey

The strongest and most comprehensive argument against pediatric experimentation belongs to Paul Ramsey. His primary thesis is such: research that does not directly benefit the child subject (i.e., is non-therapeutic) is always morally illicit. He bases this thesis on the general standpoint that experimental research should never be performed on someone who is unable to consent to it. As the argument goes, since children are incapable of consenting to inclusion in research that, by nature, does not promise direct benefit, it can never be morally justified. On the contrary, only directly beneficial research, upon the consent of parents, can be permitted. [28]

In his text The Patient as Person, Ramsey writes:

A parent’s decisive concern is for the care and protection of the child, to whom he owes the highest fiduciary loyalty, even when he also appreciated the benefits to come to others from the investigation and might submit his own person to experiment in order to obtain them. This is simply the minimum claim of childhood upon the adult community, whose members may make themselves joint adventurers or partners in the enterprise of medical advancement at cost to themselves if they will. [1525]

Here, Ramsey distinguishes between what he terms“beneficial research”—the consent to which expresses a parental fiduciary duty—and “non-beneficial research”—the consent to which is a breach of the aforementioned duty. However, he finds more than the potential exposure to risk unacceptable. For Ramsey, proxy consent to non-therapeutic research is an annulment of our right as human persons to determine for ourselves not simply the extent to which we will share
ourselves in experimentation with others, but the time and nature of such sharing. [30]

Thus, treating others as means to an end—and not,therefore, as ends in themselves, as the Kantiancontention that grounds the philosophy goes—ismorally problematic for Ramsey: “where there is no possible relation to the child’s recovery, a child is not to be made a mere object in medical experimentation.” [1512] Here, Ramsey is concerned with both the potential risk of harm as well as the violation of personal autonomy. He asserts that the moral obligation to avoid evil in the context of biomedicine outweighs any obligation to do good, and he uses this argument, based on the philosophical stance of Hans Jonas, as yet another support for his position. [29] Still, it is essentially the use of human persons as means rather than ends that is the primary foundation of Ramsey’s emphatic rejection of non-therapeutic research.

Ramsey’s argument against pediatric experimentationis intended, in the first place, to protect subjects whoare both vulnerable to being harmed by wrongful treatment and unable to consent to it. In this sense, his position must be commended. However, there are multiple objections to his general argument that are worthy of note. First, the important distinction must be made between those who refuse to consent and those who do not qualify to consent in a fully informed manner. All would agree that it is morally impermissible to force children to participate in studies of which they want no part, particularly if participation does notpromise direct benefit. However, it seems increasinglythe case that, when capable, most children are willingly to be included in medical research and, hence, have given their assent to participate. [3096]

Second, Ramsey fails to include in his argument the frequently low level of risk included in pediatric research. Since not much more risk is posed to children in medical research than exists in their everyday lives, his conclusion lacks strength in assuming the widespread prevalence of risk in all pediatric medical research. In fact, taken to the limit, Ramsey’s conclusions would omit potential studies that are only observational in nature and actually pose no risk at all. In this sense, it is much too restrictive. [3096-97]

Third, Ramsey’s position is based on the false premise that research intendedto directly benefit the subject—which he finds licit—and research intended to serve as the basis for developing further knowledge are mutually exclusive methodological approaches. Since most researchdoes not fit easily into either category, and since itis frequently the case that, regardless of prediction,research is uncertain to benefit the subjects involved, the prospect of direct benefit can hardly be ruled outfrom the beginning of “non-therapeutic” studies. Chronic disease research is one such examplethat poses, at best, a chance of benefit by virtue ofparticipation. Moreover, there are multiple ways ofinterpreting “benefit,” and a mere biophysiological interpretation is too narrow to be considered reasonable [3097].

The conceptual collapse of therapeutic and non-therapeutic research [30] sheds light on Ramsey’s shortsightedness in terms of the breadth and depth of the meaning he attributes to “research.” By definition, research is employed to gain greater knowledge into the as yet unknown. In contrast, therapy is, by definition employed to directly benefit the individual and lacks, therefore, the potential to be generally applied in other contexts. Ramsey’s concept of “therapeutic research” thus confuses two very different concepts, and such lack of clarity proves dangerous. One such danger is that if we follow Ramsey’s language (narrowly but not unreasonably) at the cost of his logic, one could never, in any circumstance, engage in “research” (e.g., the collection and subsequent interpretation of data) on the basis that it does not, of itself, provide therapy.[2897-98]

In another essay, Ramsey contends that even if pediatric experimentation would promote fidelity to the beckons of morality, “it is better to leave [this]research imperative in incorrigible conflict with theprinciple that protects the individual human person from being used for research purposes without either his expressed or correctly construed consent.” [1521] Both doing and failing to do such research is, for Ramsey, immoral, but he maintains that one must “sin bravely” by coming down on the side of preventing individual harm (by avoiding participation in research) rather than on the side of promoting societal welfare (by participating in research). However, a calculation that terminally falls on the side of preventing research is unnecessary. When minimal risk is involved, the moral calculus might reasonably be shifted to the promotion of research. [2898-99]

To be sure, children in non-therapeutic research are treated as means; but not merely as such, because the researcher is unable to use the child as she or he wishes. It is far from clear that the inclusion of children in experimental studies in which minimal risk isinvolved while substantial benefit stands to be gainedby others is obviously immoral. Since many adults feel obliged to serve others at the cost of minimal risk or inconvenience to self, it seems unreasonableto attribute an unduly sense of selfishness to childrenby virtue of age and legal status. Children certainly depend on adults for protection, but their inclusion in research seems to violate neither their dependence nor their rights unless the methods employed are foreseen to cause disproportionate harm. [2898-99]

VI. The Argument in Favor of Pediatric Experimentation on Richard McCormick

The strongest and most comprehensive argument in favor of pediatric experimentation belongs to Richard McCormick. His essential thesis is such: Children are obliged to participate in medical research because they “ought” to do something that expresses fundamental values inherent to human nature and promotes the purposes of human life and flourishing.Here, McCormick utilizes a natural law framework to ground his argument. When the research in question promises direct benefit to the subject, then consent is clearly seen to be in accord with the values inherent to human nature in that it promotes general well being. Similarly, in non-therapeutic research it is reasonable to presume, according to McCormick, that the child would consent. In light of the implicit normative ideal of health rooted in fundamental human values, contributing to the health of others would normally compel the child to do as she or he ought: participate in research and thereby promote the health of others. In other words, when the cost (i.e., risk) to the subject is minimal, consent to participation can be presumed because that is what the subject ought to do. [28100]

Since children, like all societal members, ought tobenefit others by their actions and would willinglydo so if they had the proper moral worldview, it is appropriate to include them in research so long as there exists only minimal risk. By assuming this, McCormick does not intend to argue that someone would actually act in a particular way, but only that consent may be presumed (on behalf of the child who is incapable of giving it) because the act itself is morally right. Since proxy consent is given in the therapeutic context on grounds that there exists promise of directbenefit to the health of the child subject, it can besimilarly given in the non-therapeutic context because it is based on a pediatric obligation. McCormick notes:

. . . there are things we ought to do for others simply because we are members of the human community. . . . If it can be argued that it is good for all of us to share in these experiments, and hence that we ought to do so (social justice), then a presumption of consent where children are involved is reasonable and proxy consent becomes legitimate [31].

To summarize McCormick, then: parents are the consensual vehicles by which children rightly choose what they ought, if they were so situated as to know.[28100-01]

McCormick’s argument in favor of pediatric experimentation is intended, in the first place, to promote individual and social well-being byencouraging children—through passive (parental)  presumption and active (pediatric) assent—toparticipate in relatively harmless activities that are part and parcel of living a life of justice and, hence, service to others. In this sense, his position must be commended. However, there are multiple objections to his general argument that are worthy of note.

One problem, regarding the issue of presumingchildren ought to consent, has two parts. The firstis that it claims to be embedded in a natural law argument, which is often the victim of sharp critique. Since natural law arguments rarely are framed by a general understanding of human value or purposes to which individuals should be committed (e.g., health, happiness, etc.), it does not necessarily follow that all human persons ought to want the same things, never mind directly promote them. Because all individuals do not and, moreover, probably should not, want the same things, the natural law foundation of McCormick’sargument seems deficient. This potentially renders hisentire position on pediatric experimentation normless. [28101]

The second part of the problem, much more glaringly evident, is the idea that anyone can validly presume what another is obliged to participate in and, hence, consent to. There are countless activities that adults probably ought to participate in but fail to consent to. The entire notion of obtaining consent is founded upon protecting autonomy. What is consensually appealing for one person will not be for another. Respecting persons is respecting their right to determine what is appropriate and what is not, and this is grounded in the vast differences that exist between what persons count as valuable. Even if a third party could objectively prove that something is morally binding, a value-laden personal commitment to it cannot be forced. Consent is expressive of such a commitment, and absent of this consent cannot be licitly presumed. [28102]

Following from the logic above is a second general objection to McCormick’s argument. Since it is clear that we could not typically, if ever, validly presume consent on the part of a competent adult person merely because we think she or he ought to do something, how could we possibly make the positive argument for children to do so? As Ramsey contends, McCormick’s position “amounts to the destruction of the protections consent-language was designed to afford.” [29] Only rarely can consent be presumed, and it seems illogical, if not impossible, to do so on behalf of the child subject. In brief, then, McCormick’slargest argumentative flaw seems to be at the heart ofhis logic, namely, that pediatric consent can be validly presumed. [28102] Ramsey goes on to comment that if McCormick’s proposal is adopted and subsequently standardized, then:

. . . anyone—and not only children—maylegitimately be entered into human experimentation without his will or unwillingly. . . . If a child may be treated as an adult who would will what he should, then any other nonvolunteer may be treated simply as a child who . . . would will what he should. Any non-volunteer may be treated as a child who does not will as he ought. [32]

Ramsey’s idea is that if consent can be presumed by virtue of what a third party has determined another ought to do, then (i) there exists no difference in principle between presuming consent in pediatric or adult populations, and (ii) the lack of such a difference in principle would make conscription in adults morally licit. Since McCormick agrees with adult conscription, Ramsey’s contention does not represent a direct objection from McCormick’s point of view. However, the point here is about consent, not conscription. McCormick’s thesis is that consent can be presumed if the activity in question is deemed something one ought to do, but consent is exactly what cannot be logically presumed. As history has proven, failing to solicit subjects’ consent has resulted in many moral pandemics. [28102-03]

A third problematic piece of McCormick’s argument is that it is not explicitly clear, according to his logic, that consent actually needs to be a relevant consideration.If it is the “ought” that justifies the child’s participation in a certain activity, then consent is superfluous. Inthis line of thinking, proxy consent neither validates nor invalidates the inclusion of the child and is truly irrelevant to the justification of non-therapeutic pediatric research. In other words, the two levels of argument employed by McCormick to justify pediatric experimentation include (i) natural law and (ii) consent by third parties. However, if we take the natural lawapproach as McCormick intends to employ it and find it justified, it de facto undermines the consent modelby making it gratuitous. To restate: if we are obliged to do as we ought (natural law), it is essentially irrelevant whether we agree to do it (consent). [28103-04]

It is worth mentioning here that there exists an alternative interpretation of McCormick’s argument, one perhaps more charitable and logically tidy. In later writings, McCormick appears to be anchored in the conclusion that human persons, as members of society, have a minimal moral obligation to serve their fellow members. Social circumstances, imposed from without, rather than from something inherent to human nature, create these obligations. One such obligation is submitting oneself to minimal risk for the benefit of biomedical and behavioral research, the result of which is socially productive. These social obligations imply that children, like all others, should be willing to participate in research. Parents, then, are free to consent to pediatric participation whenever the child should be willing to be included if the child could understand the implications and give informed consent. This alternative interpretation makes proxy consent a safeguard by which children are protected, though it continues to play a relatively expendable justificatory role. On this interpretation, McCormick’s position seems to be one of “presumed duty” rather than “presumed consent.” If this is correct, it becomes more appealing. [28104]

VII. Corrective Vision: A Role for Double Effect Reasoning

Although numerous positions have been put forth to nuance the arguments of Paul Ramsey and Richard McCormick, there is still room, I think, for a corrective vision that includes an application, perhaps atypical, of the principle of double effect to justify pediatric experimentation in some cases where risk is minimal (or nonexistent). [33] To be sure, the role of double effect reasoning provides neither a direct nor an exhaustive answer to perhaps the most pressing moral concern in this context: the licitness of proxy consent to non-therapeutic medical research. However, double effect reasoning may provide inroads to new ways of considering this issue.

The principle of double effect, first introduced byThomas Aquinas some seven centuries ago [34], is the method most often invoked to justify or refute practices that pose poor consequences no matter the action taken. [35] Acknowledging the complex dilemmas confronted in biomedicine, the principle’s inauguration was a concrete response to the question of whether it was morally licit to perform an action that posed polarized consequences. [36] In essence, the principle of double effect can be understood as a theoretical model and method of evaluating distinctions between two effects of an action, one right and intended, the other wrong and unintended but foreseen. The action that is right and intended can be performed in spite of the wrong and unintended but foreseen effect, if four conditions are met. [37,38]

The first condition is that the nature of the action in itself must be morally right or indifferent. Put negatively, the action must not be intrinsically morally wrong. [3745, 38] This first condition is  deontological.Circumstances and consequences aside, the action, in itself, must be morally right or indifferent; it must not be intrinsically morally wrong. As such, this condition serves as the fundamental framework for all further moral deliberation. The principle of double effect contends that if the action in itself is wrong, one need not proceed. Viewing the moral picture deontologically––and, perhaps to a fault at times, physicalistically––the question raised is whether the action is in-and-of-itself, objectively wrong. Thus, the answer to the question is clear: the action is either morally right or morally wrong, and that answer is, as noted above, independent of all other considerations. [36109]

The second condition is that the wrong effect must not cause, or be the means of achieving, the right effect. [3745, 38] This condition regards causality; the link between right and wrong actions must not begin with the wrong and end with the right. Three scenarios are possible:

1. The action causes the right effect, which in turn causes the wrong effect;

2.The action causes both the right effect and the wrong effect without either having directly caused the other; or

3. The action causes the wrong effect, which in turn causes the right effect.

The principle of double effect contends here that thefirst two scenarios are morally permissible, while the third is not, and cannot be justified morally. Since thesecond condition relies so heavily on how the actionis intrinsically specified, it is essentially reducible to the first condition. The language used to describe theaction in itself, then, is of immediate relevance. Thefirst and second conditions ensure that neither theconsequences nor the intentions might themselves be used to justify the means employed if the action is considered to be de facto wrong. [36109-10]

The third condition is that the right effect must be directly intended. Put negatively, the wrong effect, though foreseen and tolerated, must not be directly intended (and pursued as an end in itself). [3745,38] All ethicists––proportionalists, consequentialists, and deontologists alike––accept this third condition. It essentially posits that the moral agent must not intendthe wrong effect as an end to be pursued in-itself, but rather as a foreseeable and merely tolerated indirect effect, in the effort to directly and intentionally achieve the right effect. Intentionality is a complex issue that cannot be addressed in full here. However, it is worthy of note that the moral philosophical tradition has never proposed the negative connotation of the third condition to mean that the wrong effect must not be intended either as an end in itself, or as a means to that end. Rather, the principle of double effect only purports this connotation to mean that the wrong effect must not be intended as an end to be pursued in itself. Otherwise, the principle of double effect is rendered widely unhelpful, if useful at all. The concept of intentionality inherent to this third condition makes clear that people ought not want to intend the wrong effects. [36110-11]

The fourth and final condition is that the rationalefor permitting the right and intended action must justifiably outweigh the wrong and unintended consequences. In other words, there must exist proportionate reasons for permitting the wrong effect to occur that serve as the impetus for acting rather than refraining from acting. [3745,38] This condition attempts to locate proportionality in the mist of conflicting moral duties, and subsequently serves as an intellectual moral barometer that endeavors to preserve and promote right actions and minimize and reject wrong actions. It should be understood not merely as a reminder that only the most serious of reasons can justify permitting foreseen wrong effects, but as a mandate ensuring all other morally justifiable options are exhausted beforehand. [39]

Some authors have observed the principle of double effect is essentially reducible to its fourth condition, and that the use of proportionate reason, referred to theoretically as proportionalism [40], effectually makes the principle redundant. Others disagree, contending that the fourth condition, and the principle of double effect generally, can only be applied in a system of moral thought that regards some actions as intrinsically right or wrong (e.g., deontology), therebyasserting the necessity of the principle’s first condition.

For our purposes here, the latter logic will be adopted. This is not meant as an implicit comment on the philosophical legitimacy of the concept “intrinsic.” It is also not meant as an implicit comment on the validity of the former observation, the moral licitnessof proportionalism, or the reducibility of the first threeconditions to the fourth. Rather, it is simply an attempt to remain in accord with the principle of double effect,defined and understood conventionally, as a concretetheoretical method of justifying moral solutions in cases that pose polarizing consequences by virtue of the actions inherent to them, one right and the other wrong. [38301-2]

In light of the aforementioned, the first task in thecontext of pediatric experimentation is to determine thenature of the action in itself, and subsequently define itas indifferent, intrinsically right, or intrinsically wrong.

The action in question has at least two parts that must be analyzed: (i) proxy consent to experimentation and (ii) the inclusion of children in non-therapeutic research. Proxy consent is justified in many contexts, including scenarios in which persons other than the child are directlybenefited while the childis, at best, indirectly benefited. Consider a simple example that will elucidate both parts of the action in question (i.e., proxy consent and pediatric inclusion): the (dual) parental decision to keep an otherwise healthy child with a very mild temperature home from school on the basis that they do not want the child potentiallyspreading illness. In this case, the child—who does notgive assent to being kept home because she/ he needs to take an exam, wants to be with friends, and feels ok due to the relatively asympotmatic nature of the slighttemperature—may be promised indirect benefit (if onlybiophysiologically) by virtue of proxy consent while it is directly promised (even if only potentially) to the other children at school (including faculty members).

Generally, we think nothing of this direct benefitto others needing to be justified, even at the cost— defined academically, emotionally, or otherwise—tothe child who, according to this calculation, is (at most) the indirect beneficiary. Yet, this is precisely the logic, however seemingly dissimilar, employed to justify or refute non-therapeutic pediatric research. Proxy rationale in this case is that they (the parents) will not send their child to school because they do not want the child to potentially spread illness to other children, not necessarily—and, in some scenarios, at best indirectly—because it might prevent the child from developing exacerbated symptoms that would be against the child’s best interests. In this perspective, it seems only reasonable to define the nature of proxy consent to experimentation and the inclusion of children in non-therapeutic research when assent is given and potential risk minimal (or nonexistent) [41] as at least indifferent in itself if not intrinsically morally right in some contexts.

The second task is to determine if the right effect is caused by means of the wrong effect. In the context of pediatric experimentation, this essentially asks: is participation in research that does not necessarilyattribute direct benefit (i.e., is non-therapeutic) tothe willing pediatric subject, but which potentiallypromises immense direct benefit to society (the righteffect) caused by means of the potential minimal (or nonexistent) risk to which the child subject is exposed (the wrong effect)? Three scenarios are possible in our context:

1. Participation in non-therapeutic researchdirectly effects social benefit, which in turnindirectly effects exposure to potential minimal (or nonexistent) risk;

2.Participation in non-therapeutic research indirectly effects both exposure to potentialminimal (or nonexistent) risk and social benefitwithout either having directly effected the other; or

3. Participation in non-therapeutic research directly affects exposure to potential minimal (or nonexistent) risk, which in turn indirectlyeffects social benefit.

The first and second scenarios are morally justifiablewhile the third cannot be justified morally. The distinction between the notions of ‘direct’ and ‘indirect’ is of immediate relevance here. Technically, these terms can only be applied to actions post facto, that is, after they have been analyzed by the principle ofdouble effect. If the principle defines the wrong actionas ‘indirect,’ it is accepted as morally permissible. If, however, the principle defines the wrong action as‘direct,’ it is rejected as morally impermissible. This distinction allows one to designate some actions as intrinsically morally impermissible but their indirect counterparts as (or at least potentially as) intrinsically morally permissible. The idea that actions are, or may be, right is based on the ability of the direct/indirect distinction to pass the first two conditions of the principle of double effect. [36111-12] In our context, it is the initial active willingness (i.e., assent) to participate in research that directly affects the exposure to risk by which social benefit becomes possible. In other words, exposure to potential minimal (or nonexistent) risk is the indirect effect of such assent-based participation in experimentation. Outside the context of willing participation, risk itself affects nothing in particular. Thus, the first scenario above fits best. At worst, the second scenario, which is likewise morally justifiable, can be assumed.

The third task is of pivotal importance in determining the moral licitness of particular direct actions and foreseen and tolerated indirect effects. As noted above, this level of reasoning regards the notion that the right effect must be directly intended and, hence, that the wrong effect, though foreseen and tolerated, must not be directly intended as an end to be pursued in itself. According to the principle, morality mandates that right actions must be directly intended while wrong actions, though perhaps foreseen and tolerated in a limited sense, must be directly rejected. This level is essentially the logical purpose and moral binding of the principle of double effect. Applied in our context, there are at least two primary sets of intentions that must be addressed: (i) that of the parents in providing consent to participation in non-therapeutic research and (ii) that of the child subject in assenting to the aforementioned course of action.

Since we can safely assume that most parents have the best interests of their children in mind when making decisions, it is relatively simple to contend that, with proxy consent, parents directly intend the right effectof potentially benefiting society in immense fashion byallowing pediatric participation while foreseeing and tolerating the indirect and wrong effect of exposure to potential minimal (or nonexistent) risk their child may endure. Since we can also safely assume that no child would directly will her or his own harm,particularly when the potential benefit to be gleanedis essentially nonexistent, it is relatively simple to content that, with pediatric assent, children directlyintend the right effect of potentially benefiting society and the well-being of other children—say, for example,a friend or family member who is ill and in need of acure for a disease that has yet to be studied in depth—in immense fashion while foreseeing (inasmuch as

they are warned) and tolerating (insofar as they are capable) the indirect and wrong effect of enduring potential minimal (or nonexistent) risk. One such risk could be the exposure to three venipunctures over the period of one year. Clearly, neither the parents northe child directly intend the venipunctures—which, inmany cases, can hardly be calculated as a risk and, atmost, might be considered minimally harmful—but the benefit to society (perhaps a friend or family member)that might potentially result from them.

The fourth and final task concerns the notion of proportionate reason, which is essential to the moral analysis of human action. Again, this level of reasoning primarily contends that the rationale for permitting theright and intended action must justifiably outweigh thewrong and unintended consequences of the indirect effect. Put simply, there must exist proportionate reasons for tolerating the wrong effect to occur when the right effect is pursued as an end. In the absence of compelling

proportionate reasons to justify the tolerance of wrong effects, the right action and its effect, no matter how good, cannot be deemed morally licit in the full sense. At least three tiers of inquiry are operative within the fourth condition of the principle of double effect:

1. Definitional,

2. Criterial, and

3. Modal

On the definitional level, proportionate reason refersto a specific value, not a method by which to justify anaction for any reason whatsoever. As is often confused, proportionate reason does not indicate that the best method of justification is a cost-benefit analysis. Determining proportion is not analogous to solving a mathematical equation. To consider proportion, as such, inevitably leads to an essentially stringent consequentialist and utilitarian idea of the notion; this essay rejects such an interpretation. The appropriate notion of proportion as intended and employed by the fourth condition of the principle of double effect is the essence of what gives an action genuine moral meaning: the relationship shared between the meansand the end. In this sense, proportion truly defineswhat a person is doing in a given instance as it relatesto the specific value and the foreseen wrong effects that will inevitably arise trying to achieve the right effect. [42,43]

On the criterial level, proportionate reason guides in the discernment of whether a proper relationship existsbetween the specific value and the other elements ofthe action. There are three primary criteria inherent to the existence of proportionate reason in a giveninstance. The first is the means employed to achievethe value will not cause more harm than is necessary to do so. This criterion ensures that the particular value being pursued as an end must at least be equal to thevalue being sacrificed. The second criterion is thereexists no less harmful way at present to protect the value than the means immediately proposed to do so. This criterion demands that one exhaust all other options in the effort to arrive at the least harmful means of protecting the value, realizing that this determination may be required to adapt to changing circumstances in the future. The third and final criterion is the means employed to achieve the value will not logicallyundermine it. This criterion suggests, for example, that it is morally and logically illicit to obtain medication essential to the survival of one patient by indiscriminately stealing it from another patient whose life similarly depends on its providence. [42273-75]

On the modal level, proportionate reason enjoys epistemological safeguards, concretely manifested as “modes of knowing.” These modes provide the necessary certainty required to ascertain whether proportionate reasons do, in fact, exist in a givenmoral scenario. The first way of knowing whether there exists a proper relationship between the specific valuepursued as an end and the other elements of an action, is experience. This mode informs our future decisions with insights gleaned from the past. To again invoke the example above, one can deduce from experience that stealing from others undermines their well-being and the social relationships they foster. This makes stealing medication counterproductive and, hence, disproportionate. The second way of knowing whether a proper relationship exists is through one’s own sense of outrage or intuition that some actions are intrinsically disproportionate. Nonconsensual, excessive, harmful experimentation on intellectually challenged persons is one such example that wouldfall under this second mode. The third and final way of knowing is through the method of trial and error. This mode is particularly applicable to areas where experience is as yet limited but would reasonably benefit from cautious steps toward advancement, such as genetic modification in humans. [42275-76]

Applied in our context, the aforementioneddefinitional, criterial, and modal tiers provide insightinto the moral licitness of tolerating the wrong effect, exposure to potential minimal (or nonexistent) risk endured by the child, in the circumstances of proxy consent to experimentation and the inclusion of children in non-therapeutic research when assent is given and potential risk minimal (or nonexistent). Onthe definitional level, both proxy consent and pediatric assent are safeguarding tools by which social benefitfrom non-therapeutic research can be drawn. By virtue of the proper relationship that exists between the value sought and the foreseen, indirect, and unintended effect of exposure to potential minimal (or nonexistent) risk, both proxy consent and pediatric assent can be deemed proportionate. In other words, a proportionate reason exists for tolerating the wrong effect in the endeavor to directly achieve the right effect.

On the criterial level, the means used (i.e., exposureto potential minimal (or nonexistent) risk—e.g., avenipuncture) do not cause more harm than isnecessary to achieve the value (i.e., social benefit).Similarly, due to the presumption one must make that non-therapeutic research trials in pediatric populations have prospectively exhausted all other morally and medically acceptable options, there exists no less harmful way to protect the value ofbenefiting society than by proxy consent and pediatricassent to participation in experimentation. Finally, willing participation in non-therapeutic research compliments the value being sought. Used as a last resort in assentual pediatric populations with proxy consent, participation in experimentation embodies both justice and charity by serving others who are incapable of serving themselves, the product ofwhich may well prove therapeutic—understood multitudinously—to the subject.

On the modal level, we are able to ascertain from experience both that pediatric participation in non- therapeutic research has been and continues to be consonant with medicine’s healing role, and that this action can be defended as morally licit, if not explicitly encouraged, when risk is minimal (or nonexistent). Further, proxy consent to experimentation and pediatric inclusion when assent is given and potential risk minimal (or nonexistent) does not invoke a sense of outrage or intuition that the actions involved are morally disproportionate and thus illicit. If anything, the opposite senses are invoked––that of subjective harmony and objective contentedness that the right and the good are proportionately accomplished. Finally, by way of trial and error (with the methods employed in such a scenario), experience and the intuition of having achieved the value with proportionate means allows us to determine the actions involved are morally licit. Thus, they will continue to be deemed as such in similar future circumstances.

Within the context of proxy consent to experimentation and the inclusion of children in non-therapeutic research when assent is given and potential risk minimal (or nonexistent), then, exist several proportionate reasons for tolerating the wrong, indirect, and unintended effect of pediatric exposure to potential minimal (or nonexistent) risk in the effort to achieve the right, direct, and intended effect of immense socialbenefit. Thus, it can be morally justified. The fulfillmentof the four conditions (“tasks,” as I have called them) concludes the necessary criteria for determining the moral licitness of actions according to the principleof double effect. As such, we are able to confidentlyconclude that the action of pediatric experimentation is morally licit, if not explicitly encouraged, according to the principle’s reasoning, given proxy consent, pediatric assent, and exposure to potential risk minimal (or nonexistent).

VIII. Conclusion

Since Henry Beecher’s 1966 revelation of the scandal at the Willowbrook School, the conversation concerning the ethics of biomedical research, particularly including pediatric subjects, has never been the same. Throughout history, that conversation has moved from access to protection only to return to access once more. The clear and fruitful debate between Paul Ramsey and Richard McCormick in the 1970s was a forceful step toward punctuating that conversation. [44,45] Yet, today we require a vision still more careful and rational, combining the best of prudent restriction and sensible permission to combat issues surrounding the moral licitness of proxy consent toexperimentation, the qualification of pediatric assent to participation in research, and the quantification of risks and benefits in the clinical context. [1S14]

The aim of this essay has been to provide that corrective vision by positing the argument that there indeed exists a role, in certain cases, for double effect reasoning as a method by which to justify non- therapeutic pediatric research. To this end, it has been successful. The implications here are significant.Double effect reasoning in the research context maylend insight into the benefits of fostering within the moral philosophical tradition a refined understanding of what constitutes as morally normative for children in the experimentation situation. If nothing else, I have called in this essay for a reconsideration of that understanding.

The authors have disclosed no conflicts of interest.

Correspondence

Peter A. DePergola II, Ph.D., M.T.S. University of Massachusetts Medical School – Baystate College of Our Lady of the Elms peter.a.depergola@gmail.com

Correspondence

MD

Endnotes

1 Jonsen AR. Non-therapeutic Research with Children: The Ramsey versus McCormick Debate. J. Pediatr. 2006; 149:S12.

2 This is case study 16 in: Beecher HK. Ethics and Clinical Research. New Engl J Med. 1966; 274:1354-60.

3 Beecher HK. Experimentation in Man. JAMA. January 31,1959; 169:461-478.

4 Robinson WM, Unruh BT. TheHepatitis Experiments at the Willowbrook State School. In: The Oxford Textbook of Clinical Research Ethics. eds. Emanuel EJ et al. New York, NY: Oxford University Press; 2008:80.

5 Beecher HK. Ethics and Clinical Research. New Engl J Med. 1966; 274(24):1354-60.

6 For a perceptive analysis of the nature of vulnerability in research, see Ganguli-Mitra A, and Biller-AndornoN. Vulnerability in Healthcare and Research Ethics. In: Chadwick R, ten Have H, and Meslin EM, eds. The SAGE Handbook of Health Care Ethics: Core and Emerging Issues. Thousand Oaks, CA: SAGE Publications; 2011:239-50.

7 Other scholarship might indicate the beginning of this history some twenty years earlier, with the Nuremberg Trials and the ethical principles they produced. See Ross, LF. Children in Medical Research: Access Versus Protection. New York:Oxford University Press; 2006:12.

8 In agreement with Ross, David Rothman notes that “neither the horrors described at Nuremburg nor the ethical principles thatemerged from it had a significantimpact on the American research establishment” since they failedto seem “directly relevant to  the American scene.” See Rothman DJ. Strangers at the Bedside: A History of How Law and Bioethics Transformed Medical Decision Making. New York: Basic Books; 2003:62.

9 Ross, LF. Children in Medical Research: Access Versus Protection. New York: OxfordUniversity Press; 2006:12.

10 The first, concerning thehepatoxicity of the drug TriA, is case study 4 in Beecher, Ethics and Clinical Research.

11 The second, concerning an unnecessary thymectomy as part of surgery for congenital heart disease, is case study 6 in Beecher, Ethics and Clinical Research.

12 The third, concerning the aforementioned hepatitis experiments at the Willowbrook School, is case study 16 in Beecher, Ethics and Clinical Research.

13 The fourth, concerning theureteral catheterization andsubsequent radiography of newborns, is case study 22 in Beecher, Ethics and Clinical Research.

14 Beecher HK. Research and the Individual. Boston MA: Little, Brown and Company; 1970:10.

15 Ramsey P. The Patient as Person. New Haven, CT: Yale University Press; 1970: xi.

16 Ramsey would find in biomedicalscenarios dilemmas that would force one to choose between knowledge and morality “in opposition to our long-standing prejudice that the two must go together,” and would go on to argue that medical ethics necessitated “a determination of the rightness or wrongness of the action and not only of the good to be obtained. . . . Medical ethicsis not solely a benefit-producing ethics even in regard to the individual patient, since he would not always be helped without his will.” See Ramsey, The Patient as Person, xiv-xv and 2, respectively.

17 Ramsey believed the patient’s“will” was expressed only by a freely and fully informed consent. In absence of consent, there was an absence of will, and hence an absence of the partnership between researcher and subject demanded in the research context. Ramsey would describe consent as “a canon of loyalty expressive of faithfulness-claims of persons in medical intervention” by whichwould be placed “an independent moral limit upon the fashion in which the rest of mankind can bemade the ultimate beneficiary of theprocedures.” See Ramsey, The Patient as Person, 10 and 2, respectively.

18 McCormick RA. Proxy consent in the experimentation situation. Perspect. Biol Med. Autumn 1974; 18(1):9.

vhu19 The first three ensured that the research be scientifically sound, conducted first on animals andsubsequently adults prior to children and ultimately infants, and that therisks be minimized as much as possiblein both design and implementation.The final three ensured the protection of privacy and confidentiality, theequitable selection of subjects, and that the child assent, if able, to the treatment that parents or guardians must ultimately consent to. See Ross, Children in Medical Research, 23-24.

20 Subpart D of the Code of Federal Regulations 45 part 46 differentiates between research that offers and does not offer the prospect of directbenefit to the subject. See Ross, Children in Medical Research, 104.

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