Skip to main content

The Principle of the Primacy of the Human Subject and Minimal Risk in Non-Beneficial Paediatric Research

Abstract

Non-beneficial paediatric research is vital to improving paediatric healthcare. Nevertheless, it is also ethically controversial. By definition, subjects of such studies are unable to give consent and they are exposed to risks only for the benefit of others, without obtaining any clinical benefits which could compensate those risks. This raises ethical concern that children participating in non-beneficial research are treated instrumentally; that they are reduced to mere instruments for the benefit of science and society. But this would make the research incompatible with the widely endorsed principle of the primacy of the human subject (henceforth PP), which stipulates that the interests of the participating individual should prevail over the interests of science and society. This paper deals with this conflict. It analyses solutions to this problem developed in the literature, and shows that they are unsuccessful. Finally, it offers a new idea of how to reconcile the conduct of non-beneficial paediatric research with the PP. The paper argues for a new formula of the PP, and shows that it implies a specific non-comparative definition of the minimal risk threshold.

Introduction

Although the language varies slightly, almost all international guidelines and legal regulations for biomedical research involving human subjects stipulate that the interests of the participating individual should prevail (take precedence or have priority) over the interests of science and society (e.g., World Medical Association 1975-2013; World Health Organization 1995; Council of Europe, 1997a, b, 2005a, b; United Nations Educational, Scientific and Cultural Organization 2005; European Union 2001, 2014; International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use 2016; cf. table 1). This, so called, principle of the primacy of the human subject (further referred to as PP) is commonly considered as the cornerstone of research ethics (e.g. Parker 2010; Human and Fluss 2001; Andorno 2013). Despite this fact, the exact normative meaning of the PP is still a subject to a controversy (Helgesson and Eriksson 2008, 2011; Parker 2010; Pattinson 2012; Morris 2013; Emanuel 2013; Millum, Wendler, and Emanuel 2013; Różyńska 2021).

Indisputably, biomedical research is a valuable social practice “justified in terms of the good it can and often does produce” (Levine 2008, 215). The primary purpose of this practice is to develop a generalizable scientific knowledge that may contribute to progress in biomedicine and healthcare. Thus, the results of biomedical research are expected to contribute to the advancement of human health and well-being—goals highly valued by all individuals and societies. Biomedical research ultimately involves human subjects who get exposed to risks inherently associated with the studies. The risks are unavoidable as participants are offered interventions of uncertain safety and/or effectiveness. Moreover, at least some of the risks are always incurred by subjects solely for the benefit of science and society. It is because every research project, even the one with a potential to produce direct benefits to the health of participants, involves risky procedures which serve scientific purposes only (for example are aimed at better demonstrating or documenting effects of an investigational treatment).

There is widespread agreement that, although the scientific goals of research practice are very important and desirable, they must not be achieved at any cost. The few must never be sacrificed for the benefits of the many. In the predominant view the PP affirms and expresses this commitment by setting limits to the freedom of biomedical research in the name of the protection of the research subject (Council of Europe 1997b, 2005b).

Robert Andorno argues that the PP is “a direct corollary of the principle of respect for human dignity” that highlights two fundamental ideas (2009, 228). “First, that science is not an end in itself but only a means for improving the welfare of individuals and society. Second, that people should not be reduced to mere instruments for the benefit of science” (2009, 228). With regard to the latter imperative, there is universal consensus that the requirement of obtaining prior informed consent of potential participants constitutes one of the main protective mechanism against their instrumentalization in research. For obvious reasons this mechanism cannot be used in studies involving individuals unable to give consent or assent, e.g., young children. Therefore, in the context of research on such subjects, the second imperative, mentioned by Andorno (namely that people should not be reduced to mere instruments for the benefit of science) is interpreted differently, as (i) requiring consent of parents or guardians of the incompetent subject; (ii) demanding respect for the subjects’ meaningful dissent, and (iii) permitting only research “with a direct positive balance for research participants” (Helgesson and Eriksson 2008, 55), “no net risk” (Millum, Wendler, and Emanuel 2013), or which is in the participant’s best interests (Shah 2013; Piasecki, Waligora, and Dranseika 2015). However, assuming that the above interpretation is correct, it is uneasy to reconcile the last requirement derived from the PP with the conduct of non-beneficial research on incompetent subjects. By definition, subjects of such studies are exposed to risks only for the benefit of others, without their consent. Thus, it seems justifiable to claim that the participation in non-beneficial research cannot be beneficial or even neutral for the incompetent subject’s interests taken as a whole. And, therefore, it cannot be reconciled with the PP.

The conflict between the PP and the non-beneficial research on incompetent subjects, especially young children, has not yet found a satisfactory resolution in research law and ethics. Notwithstanding the PP, there is a growing consensus that non-beneficial paediatric research is necessary, socially valuable, and—in principle—ethically justified, and, consequently, that it is ethically permissible to expose subjects of non-beneficial paediatric research to some, albeit very low, risks. The ethical justification for these claims stems from the principle of beneficence and the principle of justice, applied to children as a group (National Commission 1977; Council of Europe 1997b, 2005b; European Union 2008; Council for International Organizations of Medical 2016). Non-beneficial paediatric studies should be allowed because banning them would impede progress in healthcare interventions targeting diseases and conditions to which children are susceptible and would result in exposing minor patients to interventions that are ineffective or harmful. Moreover, such a ban would unjustly deprive children from the benefits of medical progress, to which adults have access.

The main international ethical and legal standards endorse the PP while—at the same time—they allow for conducting socially valuable non-beneficial paediatric research, provided all admissibility conditions are met, especially those pertaining to substitutive consent, dissent, and level of acceptable risks. Risks involved in this category of studies must meet all general requirements for risks in human research—i.e., they must be proportional to the expected social benefits, necessary, and adequately minimized (Emanuel, Wendler, and Grady 2000). Additionally, these risks must not exceed a certain risk threshold, usually called “minimal risk standard.” The threshold sets an upper limit on permissible risks in non-beneficial paediatric research, which cannot be surpassed, no matter how valuable and probable the expected social benefits of a study are.

Although the vast majority of policymakers and research ethicists share the opinion that only low-risk non-beneficial studies on incompetent subjects are ethically acceptable, there is still a substantial amount of discussion about how to define minimal risk best. A variety of definitions has been proposed both in regulatory documents and in the literature dealing with non-beneficial paediatric research. These proposals take two general definitional patterns: (1) comparative approaches which determine the level of acceptable research risk by analogy with the risks of other activities, including: the risks of daily life (European Union 2008, 2017; Snyder, Miller, and Gray 2011; Binik 2014, 2017; Binik and Weijer 2014; Council for International Organizations of Medical Sciences 2016; U.S. Code of Federal Regulations 2018), the risks of the routine medical or psychological examination (European Union 2008, 2017; Kopelman 2004a, 2004b; Resnik 2005; Fisher, Kornetsky, and Prentice 2007; Council for International Organizations of Medical Sciences 2016; U.S. Code of Federal Regulations 2018), the risks of participating in charitable activities (Wendler 2005, 2010; Wendler and Glantz 2007), the risks of educational interventions used in family life (Ackerman 1980), or the risks of daily life situations to which scrupulous parents would intentionally expose their children (Freedman, Fuks, and Weijer 1993; Nelson and Ross 2005, DeGrazia, Groman, and Lee 2017); and (2) non-comparative approaches whereby the minimal risk threshold is defined either directly by setting a maximal acceptable level of severity and probability of research harms (Council of Europe 2005; Westra et al. 2011) or indirectly by prescribing a deliberative procedure for reaching a principled judgment on the risk acceptability (Rid 2014; Rossi and Nelson 2017). Conceptual, normative, and practical strengths and weaknesses of each of the above definitional patterns and resulting definitions have been already extensively commented upon in the literature, and they will not be repeated here. This paper will, however, emphasize the—frequently overlooked or ignored—link between the PP and the minimal risk requirement.

The overarching ethical rationale for setting the risk threshold in non-beneficial research on children unable to give consent is the need for protecting this category of subjects from being harmed only for the advantage of others, ergo from instrumental treatment. Thus, the minimal risk requirement derives from the PP. But this means that the PP should not only imply the introduction of a risk ceiling, but it should also provide normative guidelines on determining the threshold. Regrettably, the PP is rarely the subject of an in-depth normative analysis. It is even less frequently a conceptual and normative “anchor point” for the discussion on minimal risk. The discussion usually focuses on various definitions of the concept provided for in regulatory documents. But a debate limited to definitional aspects, without any reference to the ethical underpinning of the minimal risk threshold, seems incapable of reaching a consensus on the concept.

This paper deals with the described conflict between the PP and non-beneficial research on children and the normative implications of the PP for the upper limit of permissible risk in this category of studies. It aims at finding an ethically sound and fruitful interpretation of the PP rather than providing a justification for keeping the PP or removing it from the ethical and legal standards for human biomedical research. The structure of this inquiry is as follows. First, two strategies for reconciling non-beneficial paediatric research with the PP—based on the idea that participation in such studies is advantageous to the subject’s interests taken as a whole—are analysed. I argue that they both have significant conceptual or normative deficiencies that make them of little use. Then, an idea to read the PP via, the so-called, “secure child/participant standard” is investigated. It is rejected due to the lack of proper ethical justification and specificity. Ultimately, I propose to resolve the conflict between the PP and regulations allowing for non-beneficial paediatric research by developing a new formula of the PP. I offer a new definition of minimal risk, which follows from the revised PP.

Preliminary Remarks

In order to set the stage for my discussion, the scope of the inquiry needs to be clarified. Firstly, I refer to biomedical research, taken as a whole, instead of particular research interventions. I realize that any ethical analysis that fails to recognize that biomedical research often contains a mixture of non-beneficial and potentially beneficial procedures suffers from serious conceptual, normative, and practical problems. These problems have been already extensively discussed in the literature (Levine 1988; Weijer 2000). Since the “entire research” language still dominates in the international standards for biomedical research, for simplicity reasons, it will be used in this text. Nevertheless, my analysis and its conclusions shall apply to individual non-beneficial interventions, being part of any human study, as well.

Secondly, the paper focuses on non-beneficial research involving children who have no capacity to give informed consent or meaningful assent only. Thus, the inquiry excludes other groups of incompetent subjects. It also puts aside difficult conceptual and empirical questions regarding children’s decision-making competencies as well as the complex problem of the ethical significance and limits of informed consent (assent) as the main “tool” whereby an autonomous individual exercises her liberty-right to freely dispose her body, health, and even life.

Thirdly, the proposed reformulation of the PP presupposes certain account of human well-being and human interests, which will be briefly presented later in the paper. Although the account covers a variety of human interests which can be put at risk or harmed in non-beneficial research, for the sake of brevity I focus mainly on risks to subjects’ interests in preserving, restoring, or improving their physical and mental condition (referred to as health interests).

The PP, Non-clinical Benefits, and Trade-offs Between the Subject’s Interests

The PP states that the interests of the individual research subject should prevail over the interests of science and society. How should this imperative be understood? Joel Feinberg, albeit in entirely different context, suggested three ways in which this sentence may be interpreted (Feinberg 1984, 39). In the first, the subject’s interests prevail if and only if all interests of the subject are promoted by her participation in research, either equally or unequally. According to the second interpretation, in order to be consistent with the PP, it suffices for a research project to promote one or a set of particular interests of the subject, without endangering or impairing any of her other interests. Under the third interpretation, the research respects the PP when it promotes some of the participant’s interests while threatening others, “but the ones promoted are superior in some relevant way to those that are impaired, so the result is a net gain for … [the subject] on the whole” (Feinberg 1984, 39).

The first and the second way of interpretation seems difficult to apply in the context of research. As already explained, every research project exposes participants to risks which are inherent to tested drugs, devices, or procedures. It also involves risks associated with standard medical interventions (e.g. injections, biopsies, or ultrasound) performed for scientific reasons only in order to—among others—better identify, measure, or document the study results. Thus, some of the subject’s interests are always put in danger for the sake of developing socially valuable, scientific knowledge.

The third interpretation of the PP, inspired by Feinberg, seems more promising, as it accepts trade-offs between the subject’s interests. This understanding fits well into the standard justification for allowing competent individuals to enter non-beneficial studies, since those individuals are regarded as exclusively entitled to makes trade-offs between their own different interests as well as between their interests and the interests of science and society. If a competent person gives valid informed consent for participation in non-beneficial research, it is assumed that, in her best judgment, the participation is in her interest—it en bloc promotes her interests. Thus, the standard requirement to obtain informed consent from competent subjects makes such research compliant with the PP.

The third interpretation of the PP has been implicitly adopted by those numerous ethicists who try to justify the involvement of children in non-beneficial studies by arguing that while participation in this type of research puts some of the child’s interests at risk without any compensating clinical benefits, it furthers other important non-clinical interests of the subject. At least two different versions of this argument have been advocated in the literature. The first concentrates on potential benefits for children’s interests in moral and/or intellectual growth (developmental benefits argument); the second version assumes that contribution to a valuable non-beneficial paediatric study is en bloc beneficial to children as it makes their lives overall better. In what follows, I discuss each of these non-clinical benefit arguments in the context of the PP.

Risky for Health Interests but Developmentally Beneficial

The developmental benefits argument as described above assumes that the participation in non-beneficial research may promote the minor-subject’s interests, taken as a whole, since participation can contribute to the child’s interests by developing certain moral and/or intellectual capacities and these potential developmental benefits may outweigh the risks to the child’s health interests associated with the non-beneficial research.

The developmental benefits argument has been used by several authors in various guises (Bartholome 1976, 1977; Ackerman 1980; Gaylin 1982; Redmon 1986; Williams 2012). All proponents of this argument share the general conviction that participation in non-beneficial research has the potential to teach children lessons regarding the importance of helping others or altruism.Footnote 1 They, however, differ in their individual descriptions of the expected developmental benefits. For instance, Bartholome argues that participation in research may help children to “become sensitive to moral obligations and develop a disposition towards choosing that which is good” as it gives them an opportunity for actually experiencing situations in which that sensitivity is required and this disposition promoted (Bartholome 1976, 44). Ackerman agrees and adds that a child’s involvement in research may help “inculcating interests and dispositions of character in him which will allow him to become a morally good, well-adjusted and self-fulfilled adult—a ‘right kind of person’” (Ackerman 1979, qtd in Binik 2018, 3), i.e., a person having “acknowledgment of the publicly recognized moral code” (Ackerman 1980, 101). Redmon extends this argument to other benefits, such as a sense of pride in contribution to a valuable scientific project and to better understanding of how scientific research practice works (1986). For Williams, central is the potential of non-beneficial research to teach children lessons on the value and conditions of successful collaboration (2012).

Importantly, all proponents of the developmental benefits argument agree in principle that the potential developmental benefits can override risks stemming from the participation in non-beneficial research. Thus, they assume that these particular benefits may be—in a morally relevant sense—superior to potential research-related harms. Redmon explicitly stresses this fact by claiming that developmental benefits have a different nature from the majority of others good, such as money, health, or prestige. “To aid in the development of intellectual and, especially, moral abilities (or sensitivities) is to aid in the development of the individual’s autonomy” (Redmon 1986, 81). Moreover, all advocates of the argument assume that potential developmental benefits may offset only very low risks for their health interests. Thus, only such trade-offs between the minor subject’s interests are—in their view—morally acceptable.

At first glance, the developmental benefits argument seems to provide a plausible solution for the conflict between the PP and non-beneficial studies involving children. However, as shown below, the argument is vulnerable to several serious objections which make it of (at least) limited use.

The first and the most significant problem with the argument regards its scope. Both its advocates and critics note that the assumed developmental benefits may accrue only to children who already possess a certain level of cognitive capacities necessary to understand and appreciate the expected moral and/or intellectual lessons stemming from the participation in non-beneficial research (Bartholome 1976, 1977; Ackerman 1980; Redmon 1986; Williams 2012, Wendler 2010, 2012, Broström and Johansson 2014; Binik 2018). Obviously, enrolment in such research will not contribute to the moral or personal development of infants and young children who are unable to understand the concept and value of benevolence or altruism or have no capacity to comprehend scientific goals and the collaborative nature of research practice. This means that participation in non-beneficial research does not offer those children developmental benefits which could overweigh research-related risks. Ergo, it cannot result in a net gain for their interests. Consequently, non-beneficial studies on younger children do not meet the requirements of the PP and, therefore, should not be performed. This conclusion is, however, difficult to accept for both pragmatic and ethical reasons.

The second objection stems from the insufficient empirical evidence supporting the claim that non-beneficial research indeed has a potential to contribute to the moral and/or intellectual education of participating children (mature enough to learn the lesson). Some data suggest that children may derive some developmental benefits from participation in non-beneficial research. However, this data is very limited and does not allow for generalizable conclusions (Wendler et al. 2012; Luchtenberg et al. 2015; Staphorst and van de Vathorst 2015; Staphorst, Hunfeld, and van de Vathorst 2017). Additionally, as David Wendler has rightly noted, many non-beneficial studies are actually very ill suited for teaching children about altruism or the value of self-sacrifice for the benefit of others (2010, 94). This is because the risks and burdens experienced by subjects do not always contribute to the expected social benefits—some research bring insignificant or negative results; and even when they do generate positive results, subjects’ sacrifices and efforts do not directly and immediately translate into “visible” social benefits. It usually takes years for the social benefits of research to be realized and implemented. Moreover, it is almost certain that children’s abilities to appreciate the lesson involved in participation differ depending on their age, maturity, personality traits, individual history, clinical status, medical experience, and the quality of their relationships with significant others, especially parents. Thus, at present it seems reasonable to claim only that some non-beneficial research projects may offer developmental benefits to some minor subjects.

The third problem with the developmental benefits argument lies in the fact that neither proponents of the argument nor current research practice seem to actually pay attention to the realization of developmental benefits. As Linus Broström and Mats Johansson (2014) rightly point out, if children’s moral and/or intellectual development were indeed critical for the compliance with the PP, these developmental benefits should be among the reasons for children’s involvement in non-beneficial research, instead of being “a mere welcome byproduct” of their participation. Moreover, the expected benefits should be clearly articulated, promoted, and maximized and they should be realistic, not just likely to occur. In other words, a true concern for supporting children’s development through participation in non-beneficial research should have led to the creation of regulatory framework aimed at controlling factors likely to affect the realization of intended developmental goals. Clearly, depending on the exact nature of the expected benefit “some kind of research participation may be conducive to it, while other kinds will have little or no prospects of furthering the relevant development” (Broström and Johansson 2014, 57). For example, if the expected benefit is to make children more altruistic, it cannot be achieved without offering them extensive, understandable, and empathy-invoking information about the social value and scientific necessity of the research and without asking them for their assent for participating in the project. Whereas, when the goal is to develop in children an acceptance for the fact that interests of other are sometimes more important than their own, enrolling them into research without asking their assent might seem—at least in some cases—to serve better to fulfil this goal. Unfortunately, in reality neither proponents of the discussed argument, nor members of research community, including research ethics committees, nor public policymakers dealing with biomedical research are actually concerned by these issues. This fact adds strength to the conclusion that the mere fact that some non-beneficial studies may result in moral and/or intellectual growth of some children taking part in it, is not sufficient to make the practice of non-beneficial paediatric research consistent with the PP.

Risky for Health Interests But Leading to an Overall Better Life

David Wendler conceived the second strategy for reconciling the PP with the practice of non-beneficial research on children (2010, 2012). His approach builds upon the developmental benefits argument, but—in the author’s own opinion—it is superior to the latter as it does not exclude infant and very young children from non-beneficial studies. Wendler argues that participation in non-beneficial paediatric research can en bloc promote subjects’ interests, no matter their age, cognitive competences, or emotional sensitivity because it gives children an opportunity to physically contribute to a valuable project. The sole fact of making such a contribution is the source of non-clinical benefit for children, independently from their mental state or preference towards the participation. And “this is so, because having a life that includes more valuable achievements makes for a better life overall, and one of the things that is in our interests is to have a better life overall in this sense” (Wendler 2010, 133). Wendler argues further that contribution to a valuable research project can be beneficial for children in two more ways. Firstly, individuals, who contributed to valuable projects as children, may later embrace those contributions and regard them as important parts of their lives. “Moreover, the fact of having made those contributions may lead the individuals to go on to make other valuable contributions and thereby lead better lives than they would have otherwise” (Wendler 2012, 29). All these potential non-clinical benefits can outweigh some risks associated with research, though only very low ones. Consequently, the introduction of these novel benefits provides an explanation of how the conduct of paediatric non-beneficial studies can satisfy the PP.

In order to fully understand Wendler’s argument it is crucial to note that the argument is based on a specific account of human well-being (welfare, as he prefers to say) comprising of five categories of interests: (i) interests in satisficing one’s biological needs; (ii) interests in having certain experiences or states of mind while avoiding others; (iii) interests in having meaningful relationships with other persons, animals, the environment, activities, or with specific projects; (iv) interests in achieving one’s worthwhile goals (preferences, dreams, desires, plans or projects); and finally (v) interests in “human achievements, accomplishments and contributions that are valuable for us given the kinds of being we are” (Wendler 2010, 133). This last category of interests “make for a better life, all things considered” and it contains “certain things that qualify as valuable achievements” (Wendler 2010, 133), even when the individual, whose life it is, does not experience the realization of these achievements and even when these achievements do neither satisfy nor realize her personal preferences or goals. This category of objective human interests provides foundations for Wendler’s position, but—as this paper shows—it is also the main source of its weakness.

Wendler’s argument is often discussed in the literature (Singer 2011; Kopelman 2012; Spriggs 2012; Wachbroit 2012; Piasecki, Waligora, and Dranseika 2015; Binik 2018). Surprisingly enough, critics rarely focus on his assumptions regarding human nature and human interests. Instead, they stress that the argument is non-intuitive, empirically unsupported, or normatively uninteresting. For example, Ariella Binik (2018) claims that the idea that a physical, non-autonomous contribution to a valuable research makes a person’s life better, goes against commonly held moral intuitions regarding things which have any bearing on the value of human life for the individual whose life it is. This non-intuitiveness is even more evident—she adds—when the contribution to research with insignificant or negative results is considered (also Wachbroit 2012). Especially since Wendler himself stresses that the value of the contribution, for life of a person concerned, “can depend on their ultimate consequences” (2010, 193).

Loretta Kopelman (2012) challenges Wendler’s argument by pointing out unavoidable uncertainty over whether individuals will come to embrace a contribution made as children. She recognizes that Wendler allows the possibility that former participants of non-beneficial paediatric research may be ignorant, indifferent, or even regretful about their participation. Nevertheless, she rightly notes that the force of this part of his argument, which pertains to benefits coming from embracing valuable contributions done in the past, depends upon facts on how often former subjects indeed benefit it this way. The relevant data is, however, missing.

Merle Spriggs accurately notes that by limiting a priori his focus to socially valuable studies posing only low risk and involving children who cannot give consent but do not dissent either, Wendler’s argument “does not amount to anything of significance” (2012, 43).

Although these are all valid concerns, they do not touch upon the essential problem of Wendler’s position, which derives from the concept of interests in realizing “human achievements, accomplishments and contributions that are valuable for us given the kinds of being we are” (Wendler 2010, 133). This concept presupposes a substantive—though barely sketched—vision of human nature with its goods. Wendler does not deny it. He acknowledges that his account of human interests “follows from our nature” as determined by the long process of evolution; from “the kinds of being we are, the kind of mind we have” (Wendler 2010, 113). Certain things are in our interest, even when they do not affect our experiences or fulfil our preferences or even if we are unaware of their occurrence—he claims—“because of the way in which they fit into our lives, into lives that are human and good for us” (2010, 123). Wendler further suggests that affecting others and the world as whole in a positive way—i.e. “making a world a better place” (2010, 138)—is one of the human ends. On the most basic level, human beings are part of the physical world. They are influenced by the world and others and they have an influence on all things which surround them. The better they affect the world (autonomously or non-autonomously; actively or passively), the more valuable, human achievements occur in their lives, and the better their overall lives are.

These are the basic philosophical assumptions behind Wendler’s argument. I believe they cannot be accepted, at least, for the two following reasons.

Firstly, the account of human nature proposed by Wendler is far from being conceptually and normatively correct. There is nothing more controversial in philosophy than “the nature of our lives” (Wendler 2010, 136), even if it is considered as determined by the evolutionary history of our species. The mere fact that humans have certain biologically driven needs, capacities, or dispositions, does not have any significant implications for how humans ought to live and what is good for a person qua member of the species and qua an individual, whose life it is. Wendler claims that being narrow-minded, holding false beliefs (such as racism), “missing out on the richness of experience that can be gained from interactions with and understanding of a broad range of groups, cultures, ways of life, and individuals” (2010, 200), or causally contributing to a wrong cause or harming others does not fit to the nature of human life. Lives of such persons are overall worse than lives of those who are open-minded, educated, have many rich experiences, and who contribute to making the world a better place. But how do all these claims follow from our nature and our evolutionary history? Wendler seems to forget that human biology has no direct implications for normative goals of our lives. What makes human life valuable, in a morally significant sense of the word, is not set by evolution but rather by moral reflection (FitzPatrick 2021).

The second objection concerns the fifth category of human interests distinguished by Wendler—“human achievements, accomplishments and contributions that are valuable to us.” The realization of these interests—when entirely separated from individuals’ experiences, preferences, or goals—cannot be part of a plausible theory of human well-being or welfare, because the fulfilment of such “interests” does not affect an individual whose well-being is at stake. The contribution to a valuable project makes the life of a purely causal contributor (more) valuable, not because it makes the life of the contributor better for her, but because of making the lives of others, who have benefited from the project, better for them. Wendler admits that his fifth category of human interests “extends the present account beyond an account of human welfare strictly understood” (Wendler 2010, 136) and that it presupposes the existence of “an independent normative evaluation of our contributions and the impact they have on our overall lives that is independent of the contributor’s own normative evaluation of them” (Wendler 2010, 201). But why should we consider causal contributions, which neither affect the contributor nor have been embraced by the contributor, to constitute her well-being? Wendler tries to answer the latter question by arguing that the fifth category of interests is a part of our interests because we have an interest in our lives going better overall. “To have a valuable overall life is itself a significant human achievement and is realized by achieving specific human achievements that contribute to a better life overall” (Wendler 2010, 139). It is needless to say that his replay only adds on to the confusion. It raises the same question about how “an interest in our lives going better overall” can be constitutive of our well-being, when it falls into the fifth category of objectively valuable human achievements.

To summarize, Wendler’s claim that purely causal (physical) contribution to a valuable non-beneficial paediatric study makes life of a participating individual overall better for this individual, rests on shaky philosophical grounds and insufficient empirical evidence. Thus, it does not provide a valid explanation on how this category of research can be in line with the PP.

The PP and the Secure Participant/Child Standard

The deficiencies of argumentative strategies as discussed above, make certain commentators look for alternative ways of resolving the conflict between the PP and the conduct of non-beneficial paediatric research. Instead of focusing on the identification of non-clinical benefits that could outweigh research risks and result in a net gain for the subject’s interests taken as a whole, these commentators search for a new interpretation of the PP that would avoid creating contradictions.

Jan Piasecki with colleagues adopt this strategy (Piasecki, Waligora, and Dranseika 2015; also Waligora, Strzebonska, and Wasylewski. 2018). They distinguish two interpretations of the PP: strong and weak. The strong interpretation conflates the PP with the best interest standard, while the weak interpretation binds the principle with the so-called secure participant standard, i.e. a relabelled idea of the secure child standard originally developed by Seema Shah (2013). After considering numerous unsettled conceptual, normative, and practical problems stemming from the best interest standard, which have already been extensively discussed in the literature (cf. Kopelman 1997a, 1997b, 2007, 2012; Elliston 2007; Diekema 2011; Salter 2012; Shah 2013), Piasecki and colleagues argue for interpreting the PP through the lens of the secure child/participant standard which “says only that research should not expose a participant to undue, serious risk” (2015, 106).

Although, the proposed interpretation of the PP goes beyond its traditional reading, the authors fail to offer a detailed justification for their proposal. They merely support it by saying that—since the conduct of non-beneficial studies exposing children to net-risks is morally justified and accepted by all well-established ethical guidelines and regulations—it would be a hypocrisy to pretend that important interests of those subjects are not sacrificed for the good of others and to keep interpreting the PP through the lens of the best interests standard. Moreover, Piasecki and co-authors do not provide any additional explanation of the normative consequences of the proposed reading of the PP, except for concluding that it implies a requirement for setting up a limit on risk in non-beneficial research on children. Nevertheless, they do not specify the relevant risk threshold.

Regrettably, also Seema Shah—the author of the original secure child standard—does not provide any in-depth justification for the standard. She only claims that in cases when important interests of others are at stake—as it is the case with non-beneficial biomedical research—children may be exposed to “some risk of significant harm, but independent scrutiny should serve as a protection to ensure that parents do not expose their children to risk without sufficient reason” (2013, 171). Shah also admits that her proposal does not specify any ceiling of acceptable risk. However, she suggests that the special protection of the U.S. Federal regulations on paediatric research on the limits of risk as well as the requirement for ethical review will usually serve as a sufficient safeguard against exposing minor participants to unjustified or excessive risks. Thus—without providing any arguments for the claim—she takes for granted that the U.S. regulations on permissible levels of risk in non-beneficial paediatric research are consistent with the secure child/participant standard.

The PP and the Protection of the Subject’s Welfare Interests

In the above sections, I have questioned the ethical and empirical validity of the PP interpretations based on the idea that participation in non-beneficial paediatric studies is advantageous to the subject’s interests taken as a whole either because it offers developmental benefits to the child, which offset the research risks or because it makes the child’s life overall better by giving her an opportunity to contribute in valuable research projects. I have also criticized the “secure participant standard” reading of the PP for lack of proper justification and specificity. In this section I offer a new understanding of the PP and discuss its implications for the minimal risk standard. My proposal stems from the conviction that non-beneficial paediatric studies posing net-risks to the subject are, in principle, ethically acceptable and should be conducted. Thus, in order to avoid conflicts between the PP and the part of regulations that allows non-beneficial research on children, the PP should be revised.

The PP and the Child’s Welfare Interests

The PP aims at protecting the interests of research subjects, thus, in order to find an adequate interpretation of the PP, it is necessary to start with clarifying the concepts of interests and well-being. Obviously, it is not an easy task. A variety of theories of human well-being and interests has been developed in the literature (Sumner 1996; Fletcher 2016a, 2016b; Satler 2012). For the sake of this analysis, I adopt an eclectic account of human well-being and human interests, inspired by approaches developed by Joel Feinberg (1984) and Alex London (2006).

Following Feinberg, I assume that one’s interests consist of things (events or states of affairs) in which a person has a stake, meaning she stands to gain or lose depending on the nature, availability, condition, and quality of these things. “Interests, or perhaps more accurately, the things these interests are in, are distinguishable components of a person’s well-being” (Feinberg 1984, 34). Their advancement contributes to the person’s well-being, while their frustration detracts from it.

I distinguish two categories of interests: personal interests and welfare interests. Similarly to London, by personal interests I understand interests that an individual has in pursuing her particular life goals, plans, and projects that are expressions of her own personal view of what is valuable in human life. These interests are autonomy-dependent—i.e., only an autonomous person (moral agent) is able to have personal interests. They are also subjective in the sense that a particular state of affairs is in an individual personal interest only when there is a direct relationship between this individual’s mental states (experiences, preferences, desires, etc.) and that state of affairs. Consequently, non-autonomous or permanently unconscious humans cannot be subjects of personal interest. However, since in the normal course of events, children develop into autonomous adults, they may be regarded as having a potential to possess personal interests in the future.

In liberal, democratic societies individuals are free to choose from a wide range of conceptions of the good life. Thus, they may and they do radically differ in their personal interests. Following John Rawls, London notices that these potentially conflicting differences mask a “higher-order” interest shared by all members of pluralistic, liberal, and democratic societies, namely “a common ‘higher order’ in being able to pursue their individual personal interests, whatever they may be, without unwarranted interference” (London 2006, 2877). This “higher-order” interest is shared by all actual and future moral agents. However, in the case of the latter, namely children, it emanates as the “higher order” interest in developing capacities enabling them to freely choose a vision of the good life and living such a life in the future with due support by others (especially parents, educators, and appropriate public or state institutions) and free from unwarranted interference. The “higher-order” interest stems from recognition of the value (intrinsic and instrumental) of autonomous life both for individuals and societies. It provides a common ground for making moral and political decisions on the shape of social institutions and practices that have impact on individuals’ rights and well-being, including family, education, medicine, and research.

Contrary to personal interests, welfare interests are shared by nearly all human beings. They include interests in satisficing one’s physiological needs, interests in having positive experiences and mental states, and avoiding negative ones. They further include interests in having meaningful social relationships, interests in developing, maintaining, and exercising certain human capacities of physical, emotional, cognitive, and moral nature, which are necessary for autonomous and effective human agency. Finally, this category of interests comprises interests in having a certain amount of social and material resources and freedoms, which are necessary to exercise human capacities in the pursuit of one’s personal interests.Footnote 2 Thus, the category of welfare interests includes interests of humans as living, sentient animals in things or states of affairs that affect their survival and their immediate physical or affective condition (e.g., the interest in satisfying hunger, the interest in soothing pain). But, above all, the category includes interests of humans as actual or future moral agents which they possess “in virtue of having this higher-order interest in being able to pursue some determinate set of personal interests (London 2006, 2877). These interests pertain to conditions that are the necessary means for the advancement of one’s personal interests, “whatever the latter may be, or later come to be” (Feinberg 1984, 37). Without having welfare interests fulfilled, an individual’s capacities and opportunities for formulating her own vision of good life and living such a life are doomed. Thus, things which satisfy welfare interests or, at least, a vast portion of these interests, are good for a person, even if she is unaware of them, does not want them, or believes to the contrary. It this sense, welfare interests are objectively good for a person, no matter whether they are subjectively valued by the individual. The idea of welfare interests resembles Rawls’ famous concept of natural and social primary goods, that is “things that every rational man is presumed to want. These goods normally have a use whatever a person’s rational plan of life” (Rawls 1999, 54).

The account of human interests, which I adopt above, supports three ideas that are important for my further analysis. First, non-autonomous children (children who have no cognitive capacities to give informed consent or meaningful assent) have no personal interests. They have only welfare interests, including health interests, which, obviously, are of crucial importance for their actual and future well-being. Second, such children are sentient human animals, but—what is perhaps the most important—they are usually future moral agents who have a “higher order” interest in developing capacities necessary for their future effective autonomous agency, with due support and without unwarranted interference. Thirdly and finally, in the context of non-beneficial research involving children unable to give consent (assent), ethical imperatives derived from the PP should focus on the protection of welfare interests of minor subjects seen as human animals but above all, as future moral agents (provided that the target paediatric population does not include children who are entirely deprived of the potential for becoming moral agents, e.g., children with severe intellectual disabilities).

The New Formula of the PP and the Minimal Risk Threshold

After having explained the concept of human interests, I suggest that the PP should be formulated and interpreted as follows. The general formula of the PP, applicable in the context of research, should read: “The interests of science and society should never take precedence over the interests of the subject.” The proposed version of the PP is weaker than the standard formula of the PP endorsed by the majority of regulatory documents regarding biomedical research on humans. The standard version of the PP stipulates that the subject’s interests should prevail (take precedence or have priority) over the interests of science and societies. Thus, if taken literally, it requires the promotion of the subject’s interests taken as a whole. My version of the PP is less demanding. Under this new reading, the PP is satisfied when participation in non-beneficial research does not defeat interests of the subject. While this change is significant, it is fully consistent with the commonly shared position on the ethical acceptability of non-beneficial research posing net-risks to the subject’s interests. Moreover, it matches the wording of the PP as adopted by currently the most prominent international ethical standard for biomedical research on humans, namely the Declaration of Helsinki of 2013. Paragraph 8 of the Declaration stipulates: “While the primary purpose of medical research is to generate new knowledge, this goal can never take precedence over the rights and interests of individual research subjects” (World Medical Association 2013). It is also consistent with recently published results of my own historical, semantic, and normative analyses of the PP (Różyńska 2021). I conclude that the PP should be seen as a threefold concept: (i) a fundamental interpretative rule; (ii) a procedural rule, addressed mainly to research ethics committees, that imposes an obligation to carefully identify and weigh the interests of research subjects against the interests of science and society; and—what is most important for the present inquiry—(iii) a substantive (protective) rule that forbids (a) exposing interests of research participants to risks without their free and informed consent (if they are able to provide it), and (b) imposing unacceptable risks and burdens on participants’ interests that are beyond their free disposal either due to their inability to give free and informed consent or meaningful assent or due to the role-related duties of other involved parties or other value commitments (Różyńska 2021).

What are the normative implications of the proposed wording of the PP for the ethics of non-beneficial paediatric research? I argue that in the context of this category of research, the PP gives rise to the following moral imperatives:

  1. 1.

    The interests of science and society should never take precedence over the welfare interests of the child participating in non-beneficial paediatric research (especially her health interests).

  2. 2.

    The participation in non-beneficial paediatric research should not cause any permanent damages to the welfare interests of the child (especially her health interests) that are more than negligible.

  3. 3.

    Participation in non-beneficial paediatric research should not cause any temporary damage to the child’s welfare interests (especially her health interests) that are more than slight both in terms of their duration and severity.

The first imperative follows directly from the proposed general formula of the PP. The second and the third derive from moral commitments shared by all members and institutions of pluralistic, liberal, and democratic societies to (1) promote and protect the child’s “higher order” interest in developing capacities necessary for her future effective autonomous agency; and to (ii) promote and protect the “higher order” interest of the moral agent, which the child will become in the future, in being able to pursue her individual personal interests, whatever they may be. Non-negligible permanent damage and more-than-slight temporary damage to the child’s welfare interests may have a negative impact on the child’s “higher order” interest as well as on her future welfare and personal interests. Therefore, they may constitute an unwarranted interference in the child’s developmental potential and the autonomy of the moral agent, she will become. In the case of subjects who are deprived of the potential to become an autonomous moral agent, the second and third imperative finds justification in a duty to protect the current welfare interests of the child qua living, sentient human beings.

The proposed imperatives provide the rationale and certain guidelines for setting an upper limit on risks involved in non-beneficial paediatric research. These imperatives offer support for a non-comparative definition of the threshold, similar to the one adopted by the Additional Protocol to the Convention on Human Rights and Biomedicine concerning Biomedical Research (Council of Europe, 2005a). The Protocol stipulates that “research bears a minimal risk if, having regard to the nature and scale of the intervention, it is to be expected that it will result, at the most, in a very slight and temporary negative impact on the health of the person concerned” (Article 17.1). The definition from the Protocol is, however, deficient in three important respects and, as such, cannot be accepted. First, it sets a harm threshold, instead of a risk threshold. It takes into account only severity of the expected harms, while ignoring the probability (likelihood) of their occurrence (Rid 2012). Second, it focuses only on harms to health interests. Third, when read literarily, it excludes nearly all paediatric research, since one can almost never be certain that a research intervention will pose “zero” chance for more than “very slight and temporary” harm (Rid 2012; Wendler 2010, 2012). Almost all interventions bear some, typically very low, likelihood of serious harm.

In order to meet requirements stemming from the above three PP-derived imperatives while avoiding problems of the Council of Europe’s minimal risk threshold, I propose the following definition of the threshold: Participation in non-beneficial paediatric research involves only minimal risk to the child’s welfare interests if the likelihood of the research causing (i) permanent and non-negligible harms, and/or (ii) temporary harms, which are more than slight and of a short duration, is very low. Admittedly, this definition requires further clarification. It contains terms which are imprecise and open to interpretation. Regrettably, an exploration of these issues must be left to another occasion.

Conclusions

This paper deals with the conflict between the PP and the commonly accepted practice of non-beneficial research involving incompetent children. It argues that solutions to this problem developed in the literature are unsuccessful. And it offers a new idea of how to reconcile non-beneficial paediatric research with the PP. The paper argues for a new formula of the PP, and shows that it implies a specific non-comparative definition of the minimal risk threshold. Although the solution offered needs further refinement, it seems a promising approach in comparison to the regulatory and conceptual alternatives discussed in the paper. It is conceptually clear, well-grounded, and applicable in research practice.

Notes

  1. I omit here the insightful question of whether developing dispositions for helping others or being altruistic towards others constitutes a developmental benefit for the child herself at all or whether it is instead a benefit for a society (Wendler 2010).

  2. Feinberg describes these interests in the following way: “In this category are the interests in the continuance for a foreseeable interval of one’s life, and the interests in one’s own physical health and vigor, the integrity and normal functioning of one’s body, the absence of absorbing pain and suffering or grotesque disfigurement, minimal intellectual acuity, emotional stability, the absence of groundless anxieties and resentments, the capacity to engage normally in social intercourse and to enjoy and maintain friendships, at least minimal income and financial security, a tolerable social and physical environment, and a certain amount of freedom from interference and coercion ... they are the very most important interests a person has, and cry out for protection, for without their fulfillment, a person is lost. But in another way, they are relatively trivial goods, necessary but grossly insufficient for a good life” (1984, 37).

References

  • Ackerman, T.F. 1979. Fooling ourselves with child autonomy and assent in nontherapeutic clinical research. Clinical Research 27(5): 345–348.

  • Ackerman, T.F. 1980. Moral duties of parents and nontherapeutic clinical research procedures involving children. Bioethics Quarterly 2(2): 94–111.

  • Andorno, R. 2009. Human dignity and human rights as a common ground for a global bioethics. Journal of Medicine and Philosophy 34(3): 223–240.

  • ––––– 2013. The dual role of human dignity in bioethics. Medicine, Health Care and Philosophy 16(4): 967–973.

  • Bartholome, W.G. 1976. Parents, children, and the moral benefits of research. The Hastings Center Report 6(6): 44–45.

  • Bartholome, W.G. 1977. The ethics of non-therapeutic clinical research on children. In The research involving children: Appendix to Report and Recommendations. 3.1-3.22. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Washington D.C.

  • Binik, A. 2014. On the minimal risk threshold in research with children. The American Journal of Bioethics 14(9): 3–12.

  • ––––– 2017. A defense of the-risks-of-daily-life. Kennedy Institute of Ethics Journal 27(3): 413.

  • ––––– 2018. Does benefit justify research with children? Bioethics 32(1): 27–35.

  • Binik, A., and C. Weijer. 2014. Why the debate over minimal risk needs to be reconsidered. Journal of Medicine and Philosophy 39(4): 387–405.

  • Broström, L., and M. Johansson. 2014. Involving children in non-therapeutic research: On the development argument. Medicine, Health Care and Philosophy 17(1): 53–60.

  • Council for International Organizations of Medical Sciences (CIOMS) 2016. International ethical guidelines for health-related research involving humans. Geneva. https://cioms.ch/wp-content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf. .

  • Council of Europe. 1997a. Convention for the protection of human rights and dignity of the human beings with regard to the application on biology and medicine. Convention on human rights and biomedicine. CETS 164. Oviedo, Spain. https://rm.coe.int/168007cf98. Accessed December 18, 2020.

  • ––––– 1997b. Explanatory report to the Convention for the protection of human rights and dignity of the human beings with regard to the application on biology and medicine. Convention on human rights and biomedicine. https://rm.coe.int/16800ccde5. Accessed December 18, 2020.

  • ––––– 2005a. Additional Protocol to the Convention on human rights and biomedicine concerning biomedical research. CETS 195. Strasbourg, France. https://rm.coe.int/168008371a. Accessed December 18, 2020.

  • ––––– 2005b Explanatory report to Additional Protocol to the Convention on human rights and biomedicine concerning biomedical research. Strasbourg, France. https://rm.coe.int/16800d3810. Accessed December 18, 2020.

  • DeGrazia, D., M. Groman, and L. M. Lee. 2017. Defining the boundaries of a right to adequate protection: A new lens on pediatric research ethics. Journal of Medicine and Philosophy 42(2): 132–153.

  • Diekema, D.S. 2011. Revisiting the best interest standard: Uses and misuses. The Journal of Clinical Ethics 22(2): 128–133

  • Elliston, S. 2007. The best interests of the child in healthcare. Routledge.

  • Emanuel, E.J., D. Wendler, and C. Grady. 2000. What makes clinical research ethical?. JAMA 283(20): 2701–2711.

  • Emanuel, E.J. 2013. Reconsidering the Declaration of Helsinki. The Lancet 381(9877): 1532–1533.

  • European Union. 2001. Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. OJ L 121, 1.5.2001, p. 34–44 with further amendments.https://eur-lex.europa.eu/eli/dir/2001/20/2009-08-07. Accessed December 18, 2020.

  • ––––– 2008. Ethical considerations for clinical trials on medicinal products conducted with the paediatric population. Recommendations of the ad hoc group for the development of implementing guidelines for Directive 2001/20/EC relating to good clinical practice in the conduct of clinical trials on medicinal products for human use. https://ec.europa.eu/health//sites/health/files/files/eudralex/vol-10/ethical_considerations_en.pdf. Accessed December 18, 2020.

  • ––––– 2014. Regulations (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. OJ L 158, 27.5.2014, p. 1–76.https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A32014R0536. Accessed December 18, 2020.

  • ––––– 2017. Ethical considerations for clinical trials on medicinal products conducted with minors Recommendations of the expert group on clinical trials for the implementation of Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use. https://ec.europa.eu/health/sites/default/files/files/eudralex/vol-10/2017_09_18_ethical_consid_ct_with_minors.pdf. Accessed July 18, 2021.

  • Feinberg J. 1984. The moral limits of the criminal law. Vol. I: Harm to others. New York/Oxford: Oxford University Press 1984.

  • Fisher, C.B., S.Z. Kornetsky, and E.D. Prentice. 2007. Determining risk in pediatric research with no prospect of direct benefit: Time for a national consensus on the interpretation of federal regulations. The American Journal of Bioethics 7(3): 510.

  • FitzPatrick, W. 2021. Morality and evolutionary biology. The Stanford encyclopedia of philosophy (Spring 2021 Edition), ed. E. N. Zalta. https://plato.stanford.edu/archives/spr2021/entries/morality-biology. Accessed January 12, 2021.

  • Fletcher, G. 2016a. The philosophy of well-being: An introduction. London: Routledge.

  • Fletcher, G. (ed). 2016b. The Routledge handbook of the philosophy of well-being. London: Routledge.

  • Freedman, B., A. Fuks, and C. Weijer. 1993. In loco parentis: Minimal risk as an ethical threshold for research upon children. Hastings Center Report 23(2): 13–19.

  • Gaylin, W. 1982.The competence of children: No longer all or none. The Hastings Centre Report 12(2): 33–38.

  • Helgesson, G., and S. Eriksson. 2008. Against the principle that the individual shall have priority over science. Journal of Medical Ethics 34(1): 54–56.

  • Helgesson, G.. 2011. The moral primacy of the human being: A reply to Parker. Journal of Medical Ethics 37(1): 56–57.

  • Human, D. and S.S. Fluss. 2001. The World Medical Association’s Declaration of Helsinki: Historical and contemporary perspectives. Geneva: World Medical Association.

  • International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. 2016. ICH Harmonised Guideline Integrated Addendum To ICH E6(R1): Guideline For Good Clinical Practice E6(R2). https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf. Accessed December 18, 2020.

  • Kopelman, L.M. 1997a. Children and bioethics: Uses and abuses of the best-interests standard. The Journal of Medicine and Philosophy 22(3): 213-217.

  • ––––– 1997b. The best-interests standard as threshold, ideal, and standard of reasonableness. The Journal of Medicine and Philosophy 22(3): 271–289.

  • ––––– 2004a. Minimal risk as an international standard in research. Journal of Medicine and Philosophy 29(3): 351–738.

  • ––––– 2004b. What conditions justify risky nontherapeutic or “no benefit” pediatric studies: A sliding scale analysis. Journal of Law, Medicine & Ethics 32(4): 749–758.

  • ––––– 2007. The best interests standard for incompetent or incapacitated persons of all ages. The Journal of Law, Medicine & Ethics 35(1): 187–196.

  • ––––– 2012. On justifying pediatric research without the prospect of clinical benefit. The American Journal of Bioethics 12(1): 32–34.

  • Levine, R.J. 1988. Ethics and regulation of clinical research, 2nd ed. New Haven: Yale University Press.

  • ––––– 2008. The nature, scope, and justification of clinical research: What is research? Who is a subject? In The Oxford textbook of clinical research ethics, edited by E.J. Emanuel, C.C. Grady, R.A. Crouch, R.K. Lie, F.G. Miller, and D.D. Wendler, 211-221. New York: Oxford University Press.

  • London, A. 2006. Reasonable risks in clinical research: A critique and a proposal for the Integrative Approach. Statistics in Medicine 25(17): 2869–2885.

  • Luchtenberg, M., E. Maeckelberghe, L. Locock, L. Powell, and A.E. Verhagen. 2015. Young people’s experiences of participation in clinical trials: Reasons for taking part. The American Journal of Bioethics 15(11): 3–13.

  • Millum, J., D. Wendler, and E.J. Emanuel. 2013. The 50th anniversary of the Declaration of Helsinki: Progress but many remaining challenges. JAMA 310(20): 2143–2144.

  • Morris, K. 2013. Revising the Declaration of Helsinki. The Lancet 381: 1889–1890.

  • National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. 1977. Research involving children. Besheda, MA. https://repository.library.georgetown.edu/bitstream/handle/10822/559373/Research_involving_children.pdf#page=1. Accessed December 18, 2020.

  • Nelson, R.M., and L.F. Ross. 2005. In defense of a single standard of research risk for all children. The Journal of Pediatrics 147(5): 565–566.

  • Parker, C. 2010. The moral primacy of the human being. Journal of Medical Ethics 36(9): 563–566.

  • Pattinson, S.D. 2012. Emergency research and the interests of participants. Medical Law International 12(2): 121–141.

  • Piasecki, J., M. Waligora, and V. Dranseika. 2015. Non-beneficial pediatric research: Individual and social interests. Medicine, Health Care and Philosophy 18(1): 103–112.

  • Rawls, J. 1999. A theory of justice, revised ed. Cambridge, MA: Belknap Press.

  • Resnik, D. 2005. Eliminating the daily life risks standard from the definitione of minimal risk. Journal of Medical Ethics 31(1): 35–38.

  • Redmon, R.B. 1986. How minors can be respected as ends yet still be used as subjects in non-therapeutic research. Journal of Medical Ethics 12(2): 77–82.

  • Rid, A. 2012. Risk and risk-benefit evaluations in biomedical research. In Handbook of risk theory. Epistemology, decision theory, ethics, and social implications of risk, edited by S. Roeser, R. Hillerbrand, P. Sandin, and M. Peterson, 179-211. Springer Science+Business Media B.V.

  • ––––– 2014. Setting risk thresholds in biomedical research: Lessons from the debate about minimal risk. Monash Bioethics Review 32(1-2): 63–85.

  • Rossi, J. and R.M. Nelson. 2017. Minimal risk in pediatric research: a philosophical review and reconsideration. Accountability in Research 24(7): 407–432.

  • Różyńska, J. 2021. Taking the principle of the primacy of the human being seriously. Medicine, Health Care and Philosophy 24(4): 547–562.

  • Salter, E.K. 2012. Deciding for a child: A comprehensive analysis of the best interest standard. Theoretical Medicine and Bioethics 33(3): 179–198.

  • Shah, S. 2013. Does research with children violate the best interests standard? An empirical and conceptual analysis. Northwestern Journal of Law and Social Policy 8: 121–173.

  • Singer, P. 2011. When is research on children ethical? The Lancet 377(9760): 115–116.

  • Snyder, J., C. Miller, and G. Gray. 2011. Relative versus absolute standards for everyday risk in adolescent HIV prevention trials: Expanding the debate. The American Journal of Bioethics 11(6): 5–13.

  • Spriggs, M. 2012. Justifying pediatric research not expected to benefit child subjects. The American Journal of Bioethics 12(1): 42–44.

  • Staphorst, M., and S. van de Vathorst. 2015. Empirical data on benefits children experience in clinical research. The American Journal of Bioethics 15(1): 20–21.

    Article  Google Scholar 

  • Staphorst, M.S., J.A. Hunfeld, and S. van de Vathorst. 2017. Are positive experiences of children in non-therapeutic research justifiable research benefits? Journal of Medical Ethics 43(8): 530–534.

  • Sumner, L.W. 1996.Welfare, happiness, and ethics. Oxford University Press.

  • United Nations Educational, Scientific and Cultural Organization (UNESCO). 2005. Universal Declaration on bioethics and human rights. http://portal.unesco.org/en/ev.php-URL_ID=31058%26URL_DO=DO_TOPIC%26URL_SECTION=201.html. .

  • U.S. Code of Federal Regulations. 2018. U.S. 45 Code of Federal Regulations §46.102(j) (Subpart A: Basic HHS Policy for Protection of Human Research Subjects); §46.401–409 (Subpart D (Additional policy for children involved as subjects in research). https://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=83cd09e1c0f5c6937cd9d7513160fc3f&pitd=20180719&n=pt45.1.46&r=PART&ty=HTML#se45.1.46_1102. Accessed December 18, 2020.

  • Wachbroit, R. 2012. On Wendler’s new justification for pediatric research. The American Journal of Bioethics 12(1): 40–42.

  • Waligora, M., K. Strzebonska, and M.T. Wasylewski. 2018. Neither the harm principle nor the best interest standard should be applied to pediatric research. The American Journal of Bioethics 18(8): 72-74.

  • Weijer, C. 2000. The ethical analysis of risk. The Journal of Law, Medicine & Ethics 28(4): 344–361.

  • Wendler, D. 2005. Protecting subjects who cannot give consent: Toward a better standard for minimal risk. Hastings Center Report 35(5): 37–43.

  • ––––– 2010. The ethics of pediatric research. New York: Oxford University Press.

  • ––––– 2012. A new justification for pediatric research without the potential for clinical benefit. The American Journal of Bioethics 12(1): 23–31.

  • Wendler, D. and L. Glantz. 2007. A standard for assessing the risks of pediatric research: Pro and con. The Journal of Pediatrics 150(6): 579–582.

  • Wendler, D., E. Abdoler, L. Wiener, and C. Grady. 2012. Views of adolescents and parents on pediatric research without the potential for clinical benefit. Pediatrics 130(4): 692–699.

  • Westra, A.E., J.M. Wit, R.N. Sukhai, and I.D. de Beaufort. 2011). How best to define the concept of minimal risk. The Journal of Pediatrics 159(3): 496–500.

  • Williams, G. 2012. Children as means and ends in large-scale medical research. Bioethics 26(8): 422–430.

  • World Health Organization (WHO). 1995. Guidelines for good clinical practice (GCP) for trials on pharmaceutical products. Geneva.

  • World Medical Association (WMA). 1975. Declaration of Helsinki. Recommendations guiding medical doctors in biomedical research involving human subjects. Tokyo, Japan. https://www.wma.net/wp-content/uploads/2018/07/DoH-Oct1975.pdf. Accessed December 18, 2020.

  • ––––– 2013. Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects. Fortaleza, Brazil. https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/. Accessed December 18, 2020.

Download references

Funding

This analysis was supported by a grant of the National Science Centre, Poland, no. 2014/15/B/HS1/03829.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joanna Różyńska.

Ethics declarations

Conflicts of Interest

I have no conflict of interests or competing interests to disclose.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Różyńska, J. The Principle of the Primacy of the Human Subject and Minimal Risk in Non-Beneficial Paediatric Research. Bioethical Inquiry 19, 273–286 (2022). https://doi.org/10.1007/s11673-022-10179-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11673-022-10179-7

Keywords

  • Ethics of non-beneficial paediatric research
  • The primacy of the human being
  • Instrumentalization
  • Minimal risk standard