The basic ethical principles identified by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1) as those that should underlie the conduct of research involving human subjects are “respect for persons,” “beneficence,” and “justice.” These principles were endorsed subsequently by the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research (2) as “basic values” for medical practice as well as for biomedical and behavioral research, calling them by somewhat different names: “respect,” “well being,” and “equity.” According to these authoritative commissions, research involving human subjects should be conducted in accord with norms or rules designed to uphold and embody these basic principles or values. These rules are assembled in federal regulations for the “protection of human research subjects”; most relevant to the present concerns are those of the Department of Health and Human Services (Code of Federal Regulations, Title 45, Part 46; hereafter abbreviated as 45 CFR 46)¹ and the Food and Drug Administration (Code of Federal Regulations, Title 21, Parts 50 and 56; hereafter abbreviated as 21 CFR 50 and 21 CFR 56).

In this chapter there are frequent references to federal regulations. This is not intended to suggest that all ethical considerations are reflected adequately in the law. Rather, the regulations in this field generally represent a broad social consensus about what ought and ought not to be done. Even for research not covered by the regulations, they have come to be regarded as establishing a community standard, departures from which require justification (3). The regulations include both substantive and procedural rules (norms). A substantive rule specifies behaviors that are required (or forbidden) because they are morally right (or wrong). Some procedural rules specify procedures that should be performed to determine the most appropriate behavior when the behavior has not been specified by a substantive rule. Other procedural rules are designed either to assist in the adherence to the requirements of a substantive rule or to provide documentary evidence that
research has been conducted in accord with the relevant substantive rules (3).

The principle of respect for persons requires that human persons must be treated as autonomous agents. The substantive norm that requires informed consent is a specification of one way in which this principle is to be made operational in the conduct of research involving human subjects. The procedural norm that requires review and approval by an institutional review board affords a method for determining what specific bits of information must be divulged to prospective subjects in a particular research protocol. Another procedural norm that requires the signing of a consent form provides documentary evidence that the behavior required by the substantive norm has been accomplished. The form itself assists the investigator’s efforts to comply with the substantive rule.

To show respect for autonomous persons requires that we leave them alone, even to the point of allowing them to choose activities that might be harmful (e.g., hang gliding), unless they agree or consent that we may do otherwise. We are not to touch them or encroach on their private spaces unless such touching or encroachment is in accord with their wishes. Our actions should be designed to affirm their authority and enhance their capacity to be self-determining; we are not to obstruct their actions unless they are clearly detrimental to others. We show disrespect for autonomous persons when we either repudiate their considered judgments or deny them the freedom to act on those judgments in the absence of compelling reasons to do so.

Clearly, not every human being is capable of self-determination. The capacity for self-determination matures during a person’s life; some lose this capacity partially or completely, owing to illness or mental disability or in situations that severely restrict liberty, such as prisons. Respect for the immature or incapacitated may require one to offer protection to them as they mature or while they are incapacitated.

Because the central focus of this chapter is on respect for persons, it is necessary to emphasize that the other two principles are of equal importance in the sense that they have equal moral force. Research involving human subjects can be considered ethically justified if, and only if, it is adequately responsive to each of the three basic ethical principles (3). As we shall see, considerations of justice and beneficence place constraints on, for example, whom we can ask to serve as research subjects and how much risk we may ask them to accept in the interests of research.

Principle I of the Nuremberg Code (4) provides the definition of consent from which definitions supplied in all subsequent codes and regulations are derived:

Thus, consent is recognized as valid if it has each of these four essential attributes: It must be competent (legally), voluntary, informed, and comprehending (or understanding).

It is through informed consent that the investigator and subject enter into a relationship, defining mutual expectations and their limits. This relationship differs from ordinary commercial transactions in which each party is responsible for informing himself or herself of the terms and implications of any of their agreements. Professionals who intervene in the lives of others are held to higher standards. They are obligated to inform the layperson of the consequences of their mutual agreements.

It is worth noticing that the Nuremberg Code defines and requires “voluntary consent.” Since 1957 this term has been replaced by “informed consent,” a term that reflects an idealized vision of the person as a rational, self-determining agent (5).

Federal regulations identify “elements” of information that must be transmitted during the negotiations for informed consent (45 CFR 46.116a); these are:

In addition, according to the regulations, the following elements must be provided “when appropriate” (45 CFR 46.116b):

The regulations define only minimum standards for informed consent. In most cases it seems appropriate to supplement these basic requirements with additional elements of information (3). For example, prospective subjects should be told why they have been selected as invitees to participate in the research; ordinarily, this consists of a statement of the major inclusion and exclusion criteria for the protocol. In addition to the statement of “additional costs to the subject” required by the regulations, there should also be accurate statements of any cash payments or other economic advantages associated with participation in the research as a subject.

How does one determine whether any particular fact (e.g., any particular risk of injury) must be disclosed? The legal criterion for disclosure in the context of medical practice is “material risk,” that is, any fact that is material to the patient’s decision must be disclosed (3,6). The determination of which risks are material in that they must be disclosed may be accomplished according to three different standards or tests (3,7). Until recently, the prevailing standard was that of the “reasonable physician”; the determination of whether any particular risk or other fact should be disclosed was made on the basis of whether it was customary to do so in the community of practicing physicians.

The standard that is now applied most commonly is the “reasonable person” or “prudent patient” test. In the case of Canterbury v. Spence (8), the court held that the disclosure required was determined by the patient’s right of self-decision, a right that can be effectively exercised only if the patient possesses enough information to enable an intelligent choice. A risk is thus material when a reasonable person, in what the physician knows or should know to be the patient’s position, would be likely to attach significance to the risks or cluster of risks in deciding whether or not to forego the proposed therapy.

Some courts have adopted the rule that a risk is material if the particular patient making the choice or decision considers it material. Of the three standards, this rule, which some call the idiosyncratic person standard, is most responsive to the requirements of the ethical principle of respect for persons. It is, however, a highly impractical standard.

In the author’s view, the reasonable person standard should determine the minimum amount of information that should be imparted by the researcher to each and every prospective subject. Then, in the course of the consent discussions, the researcher should attempt to learn from each prospective subject what more he or she would like to know.

Federal regulations permit “a consent procedure which does not include, or which alters, some or all of the elements of informed consent” or, in some cases, waiver of the entire requirement for informed consent, if:

Implicit in these conditions— particularly the second condition— is recognition of the standard of materiality. One may not withhold any material information without adversely affecting the rights of subjects. Waivers and alterations are commonly used in research involving medical records, “leftover” specimens of tissues and body fluids from which personal identifying information has been removed, survey research, and so on. It is more problematic when researchers propose to alter information for purposes of deceiving prospective research subjects (3).

The Department of Health and Human Services (DHHS) makes it clear that, “Nothing in these regulations is intended to limit the authority of a physician to provide emergency medical care, to the extent the physician is permitted to do so under applicable federal, state, or local law” (45 CFR 46.116f). Implicit in this rule is a recognition of two exceptions to the legal requirement for informed consent: the emergency exception and therapeutic privilege.²

The Food and Drug Administration (FDA) permits waiver of the consent requirement for the use of investigational new drugs (or other regulated test articles) in the treatment of individuals in “life-threatening situations” in which “informed consent cannot be obtained…because of an inability to communicate with, or obtain legally effective consent from, the subject” (21 CFR 50.23). There is also a provision in FDA regulations for an exception from informed consent requirements for emergency research; this exception is designed for research activities in which most or all of the prospective subject population will be unable to consent and it will not be feasible (usually owing to lack of time) to get consent from a legally authorized representative (21 CFR 50.24).³

Thus far we have been considering informed consent, a process designed to show respect for subjects, fostering their interests by empowering them to pursue and protect their own interests. The consent form, by contrast, is an instrument designed to protect the interests of researchers and their institutions by defending them against civil or criminal liability. I believe that one of the reasons there has been so little successful litigation against investigators, as compared with practicing physicians, is the very formal and thorough documentation of informed consent on consent forms. Consent forms may be detrimental to the subject’s interests not only in adversarial proceedings; signed consent forms in institutional records may lead to violations of privacy and confidentiality (3).

Although the primary purpose of the consent form is to protect the interests of researchers and their institutions, it is forbidden by federal regulations to:

DHHS requires that “[a] copy shall be given to the person signing the form” (45 CFR 46.117). The primary purpose of the form notwithstanding, it can and should be designed to be helpful to the subjects. Having a copy of the form will afford them an opportunity to continue to get more information as additional questions occur to them. It can also serve as a reminder of the plans they must follow in order to accomplish the purposes of research, of the symptoms they should watch for to protect their own safety, of the perils of omitting doses of drugs, and so on. It can serve as a guide to conversations they might choose to have with family, friends, personal doctors, and other trusted advisors about whether they should consent; in some cases such conversations should be recommended during the consent negotiations. In the use of these forms, however, the researcher should heed the words of the President’s Commission (9): “Ethically valid consent is a process of shared decision-making based upon mutual respect and participation, not a ritual to be equated with reciting the contents of a form that details the risks of particular treatments.”

No consent form can be designed so as to anticipate all of any particular prospective subject’s wishes to be informed. The consent form is most effective when it is viewed by the researcher as a guide to the negotiations with the prospective subject. The consent form should contain at least the minimum amount of information and advice that should be presented during the negotiations. If any substantive new understandings are developed in the process of negotiations that have any bearing on the prospective subject’s willingness to participate, these should be added to the consent form signed by that individual.

DHHS regulations (45 CFR 46.117) permit waiver of the requirement for documentation of informed consent if:

In some cases in which the regulations permit waiver of the requirements for documentation, it may be advisable to provide subjects with information sheets. These documents provide a written account of all information that could serve subjects’ interests in ways suggested earlier. They differ from consent forms primarily in that they are not signed by subjects and retained by researchers. Thus, they afford limited protection to the researcher and the institution.

Children, as a class of persons, lack the legal capacity to consent. Moreover, many of them, particularly the younger ones, are not only incapable of sufficient comprehension to meet the Nuremberg Code’s standard but are also not “so situated as to be able to exercise free power of choice.” It is necessary to rely on other devices to show respect for children because they cannot consent. Two of these devices are permission and assent.

Permission of one or both parents or of the legal guardian is closely related to what was formerly called proxy consent. With few exceptions, federal regulators regard permission as a necessary condition for authorizing the involvement of a child as a research subject; for children who cannot assent, it is usually a sufficient condition as well. The transactions involved in negotiating a valid permission are in all respects identical to those of informed consent.

Assent by the child should be as close an approximation of consent as the child’s capabilities permit.

Before proceeding with our discussion of permission and assent, it is necessary to return to a consideration of the basic ethical principles.

Respect for persons requires that we treat individuals as autonomous agents only to the extent that they are autonomous. As noted earlier, “[p]ersons with diminished autonomy and thus in need of protection are entitled to such protections (1).” In response to this ethical conviction, there is established in federal regulations a standard called “minimal risk,” which “means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests” (45 CFR 46).⁶ Minimal risk serves as a threshold standard in that plans to involve children in research that presents more than minimal risk require special justification and procedural protections.

But many therapeutic procedures present far more than minimal risk, and it is not customary to obstruct children’s access to them by calling for special procedural protections. The regulations make it clear that the minimal risk standard is applicable only to procedures that do not “hold out the prospect of direct benefit for the individual subjects” (45 CFR 46.405). Therapeutic procedures, by contrast, are to be authorized and justified precisely as they are in the practice of medicine. That is to say, the risk of any procedure is justified in terms of the benefit expected for the individual child-subject who will bear that risk. Also, as in medical practice, the relationship of anticipated benefit to the risk presented by the procedure must be at least as advantageous to the subject as that presented by any available alternative, unless, of course, the subject (or his or her parents) has considered and refused to accept a superior alternative. These rules are responsive to the ethical principle of beneficence, which as articulated by the National Commission (1) is expressed in the form of two general rules: “(1) Do no harm; and (2) maximize possible benefits and minimize possible harms.”

Justice, as envisioned by the National Commission, requires a fair sharing of the burdens and benefits of society (1,3). In the distribution of these burdens and benefits, special consideration is to be given to those who are vulnerable or disadvantaged. Children are considered vulnerable and are to be protected from exploitation because they lack the capacity to consent. They are not to be involved in research that is irrelevant to the class of person of which they are representative. When appropriate, research should be done first on adults and then on older children before involving younger children and infants (3).

In summary, children and their parents are not completely free to do their own thing. There are constraints grounded in ethical considerations and enforced by regulations regarding whom researchers may invite to serve as subjects and how
much risk they may be asked to assume for research purposes. With these constraints in mind, we now turn to further consideration of assent and permission.

Respect for children does not require that we leave them alone even to the point of allowing them to choose dangerous activities unless they agree that we may do otherwise. Young children have no such liberty rights. What they have instead is a right to custody (10). We show respect for them by fostering their well being, protecting them from harm, and guiding them to become “the right kind of people.”

As we have already noticed, federal regulations reflect the obligation to protect children from harm and to secure their well being. Let us now consider the obligation to guide their moral and social development— an obligation not recognized explicitly in the regulations.

In the 1970s there was a spirited debate over the legitimacy of using persons who are incapable of consent (“unconsenting subjects”) as research subjects. Paul Ramsey (11) argued that it is always morally wrong. Richard McCormick (12), arguing the opposing viewpoint, pointed out that members of a moral community have certain obligations. One of these is to contribute to the general welfare when to do so requires little or no sacrifice. In the case of children, one may presume that they would consent if they could; he calls this a “correctly construed consent.” In his view, when supplemented with parental permission, correctly construed consent authorized the use of children as subjects in research that fulfilled an important social need and involved “no discernible risk.”