Ethical Considerations in Pediatric Oncology
Steven Joffe
Jennifer Kesselheim
Susan Shurin
INTRODUCTION
Few fields are as rich in ethical challenges as pediatric oncology. We want both to be truthful with the child who has cancer and to respect parents’ roles in guiding their families. We want to honor families’ religious beliefs while ensuring that a child does not die for lack of a blood transfusion. We want to avoid burdensome interventions at the end of life while keeping open any possibility that the child may recover.
Understanding of and commitment to ethical values and principles are central to professionalism in medicine and research. Fundamental principles include the primacy of patient welfare, respect for patient autonomy, and social justice.1 Specific obligations include commitments to honesty with patients and families, confidentiality, respect for appropriate boundaries, a just distribution of finite resources, and management of conflicts of interest (COI). Increasing evidence suggests that professionalism can be taught and learned.2
In what follows, we concentrate on select areas relevant to clinicians and investigators caring for and conducting research with children with cancer. We begin with discussions of informed consent and of the ethics of research with human participants. This is followed by comments on confidentiality, genetic testing, and ethics in end-of-life care. Finally, we consider financial incentives and COI.
INFORMED CONSENT
Few areas of bioethics have evolved as dramatically over the past 50 years as have conceptions of the rights and responsibilities of patients and their physicians. The Hippocratic Oath adopts a paternalistic stance, directing physicians to “use treatment to help the sick according to my ability and judgment, but…never use it to injure or wrong them.”3 Over time, both physicians and patients have come to expect that patients will have information and participate in decision making. Respect for persons, or respect for autonomy, is operationalized in the practice of informed consent. As evidence and options have increased, the concept of consent—meaningful only when informed—has acquired a central place in bioethics.
Scattered legal cases from the 1700s to the early 1900s emphasized the need for consent—usually without considering how or whether the patient became informed—and viewed infractions of the consent requirement as tantamount to battery. Since the mid-1900s, legal cases have developed the requirement for informed consent, and consequently for sufficient disclosure by the physician about the material facts.4,5,6 The mandate that consent be informed was not firmly established in U.S. case law until 1957.7 The contemporary legal system generally treats violations of the disclosure requirement as professional negligence rather than as battery.
The historical origins of consent to treatment and to research differ. Consent to treatment evolved as a legal doctrine, as patients successfully brought malpractice actions for violations of consent. In contrast, the requirement for consent to research developed through a combination of ethical codes—beginning with the Nuremberg Code in response to the Nazis’ abuses8—and prospective regulation of research.9
In pediatrics, many conversations and decisions take place between clinicians and parents, with increasing involvement of children as they mature. Pediatric oncology practice brings additional challenges, given the high proportion of pediatric oncology patients cared for within trials and the fact that investigators enrolling patients are often also the clinicians responsible for their care. Navigating this terrain requires a nuanced understanding of consent to both clinical care and research, and an appreciation of distinctions where they exist.
We start with the simplest case—the competent adult deciding about nonresearch clinical care—before addressing consent in pediatrics. We discuss the special issues raised by consent to research in the section on research ethics, later in the text.
Informed Consent for Competent Adults
The doctrine of informed consent is most straightforward when applied to individuals “of adult years and sound mind.”10 Five criteria together constitute valid informed consent: (a) voluntariness, (b) capacity, (c) disclosure, (d) understanding, and (e) decision.11
Competence and Capacity
Competence and capacity are often used interchangeably. Competence describes a person’s legal authority to manage her or his own affairs in a particular domain of life. Capacity denotes the perceptual, cognitive, and communicative ability to perform a particular task. It reflects a clinical rather than a legal judgment, and therefore falls within the domain of clinicians with appropriate expertise. Thus, although the average older teen may have capacity to make most medical decisions, the teen will be presumed legally incompetent in most jurisdictions.
Decision-making capacity can be judged in relation to four abilities: (a) the ability to make a choice; (b) the ability to understand relevant information; (c) the ability to appreciate the consequences of a decision for one’s situation; and (d) the ability to manipulate information rationally.12 Many clinicians take a “sliding scale” approach to capacity determinations, whereby standards become increasingly stringent as the consequences of a decision and the degree to which it deviates from what seems reasonable increase.13
Disclosure
Disclosure refers to the information that must be communicated to the patient, including: (a) the nature and purpose of the proposed treatment; (b) the foreseeable risks and discomforts; (c) the potential benefits; and (d) available alternatives. Any reasonable interpretation recognizes the need for selectivity in the amount and type of information shared.14 Common complications should be disclosed regardless of severity, and serious or irreversible risks should be disclosed regardless of frequency.
Three standards are available to guide physicians in deciding what information to present to patients. Two are used by courts to determine whether physicians have met their disclosure
requirements. Under the professional standard, the physician must provide the information that a reasonable physician would disclose in similar circumstances. Under the reasonable-person standard, the physician must provide all the information that a reasonable decision-maker would want to know (i.e., that is material to the decision). A third standard, the subjective standard, is an ethical ideal without a specific legal correlate. Under this standard, the clinician should provide information that is material not just for a reasonable person, but for this particular person. Although the rare risk of mild peripheral neuropathy may not be a major issue for most, it may be crucial to a professional pianist. Meeting this standard requires that the physician know the patient well enough to anticipate that such information would be subjectively relevant.
requirements. Under the professional standard, the physician must provide the information that a reasonable physician would disclose in similar circumstances. Under the reasonable-person standard, the physician must provide all the information that a reasonable decision-maker would want to know (i.e., that is material to the decision). A third standard, the subjective standard, is an ethical ideal without a specific legal correlate. Under this standard, the clinician should provide information that is material not just for a reasonable person, but for this particular person. Although the rare risk of mild peripheral neuropathy may not be a major issue for most, it may be crucial to a professional pianist. Meeting this standard requires that the physician know the patient well enough to anticipate that such information would be subjectively relevant.
Understanding
It is easier to determine what a clinician has disclosed than what a patient has understood. Even when disclosure is exemplary, understanding can be elusive, particularly in settings such as pediatric oncology in which emotions can so profoundly influence patients’ and parents’ decision making. Courts generally look to evidence of disclosure rather than of understanding to judge the adequacy of consent. Nevertheless, understanding remains an ethical aspiration.
To achieve shared decision making, clinicians should regularly assess patients’ understanding of the diagnostic and treatment alternatives. This can be particularly difficult around choices involving risk. Individuals will choose different treatments, depending on whether the risks are presented as the probability of success or of failure.15 Such framing can have powerful consequences when, for example, a clinician presents a preferred option in terms of its chances for disease control while presenting the alternatives in terms of their probabilities of recurrence.
Voluntariness
To be valid, consent must be free as well as informed. Choices can be influenced by persuasion or coercion. Physicians may ethically employ persuasion.16 When, for example, a patient refuses chemotherapy for a potentially curable malignancy because of concerns over side effects, the physician may ethically attempt to persuade the patient to accept chemotherapy.
Coercion involves the use of credible threats to influence decisions.17 For example, a clinician may tell parents that, if they refuse chemotherapy, hospital attorneys will seek a court order to initiate treatment. Involving outside authorities should only be considered when efforts at persuasion have failed. Punitive threats, such as refusing to treat pain unless parents agree to the physician’s preferred treatment regimen, are always unjustified. Finally, only decisions that put others at risk (e.g., harm to third parties from a contagious disease) justify the use of coercion to influence the decision of a competent adult patient.
Decision
It is tempting to view consent as signature on the bottom of a form. However, the protracted nature of cancer treatment underscores the point that informed consent is a process—an ongoing conversation between the patient, caregivers, and a team of clinicians—not a discrete event.18
Informed Consent, Surrogate Authorization, and Incompetent Adults
The model of autonomous consent for medical decision making has dominated other possible models. The law has sought to define ways in which partially or fully incapacitated patients can exercise these rights indirectly via surrogates.
Two standards have evolved to guide decision making by surrogates. The substituted-judgment standard seeks decisions based on actual values and preferences that patients had before becoming incompetent. Substituted judgment is most readily implemented when the incompetent person’s wishes are known or can be inferred; it fits poorly when making decisions for never-competent persons, including young children, or for those whose wishes cannot be deduced.19
The desire to base decisions on patients’ actual wishes has motivated efforts to have patients articulate these wishes through advance directives before they lose capacity. One type of directive, the living will, allows patients to specify the extent to which they would like to have life-sustaining medical treatments provided should they develop specific medical problems while incompetent. Living wills have proved problematic, however; few people complete them, individuals have difficulty predicting their wishes in serious and unfamiliar circumstances, it is difficult to articulate those preferences, and clinicians and surrogates do not reliably act on them.20 An alternate approach is the health care proxy, a document that assigns decision-making authority to a particular person in the event of incapacity. Hospitals in the United States must inquire whether adult patients currently have an advance directive, and must give them an opportunity to create one if they do not.21
The best-interests standard is generally used for patients who never have been competent or whose preferences about care are not known. It is the most appropriate standard to guide decisions for young children. Although this standard provides useful guidance for surrogates, it does not resolve situations in which views about how best to advance the interests of affected patients differ, and does not adequately clarify surrogates’ range of discretion. To address these problems, Diekema22 has proposed that, when patients’ wishes are unknown, proxies’ decisions should be respected unless there is convincing evidence that those decisions place the patients “at significant risk of serious preventable harm.” Determining the best interests of children is complex, incorporating physical, emotional, mental, and social factors. When these components are not aligned, identifying the best interests of the child can be among the most difficult ethical decisions facing family and other caregivers.
Informed Consent and Children
Analyses of medical decision making for children often begin with the conceptual model of the noncompetent patient. Most sentinel legal cases involving adults concerned patients who never were expected to regain capacity. In contrast, children’s decision-making capacity is usually growing. We seek to respect the former autonomy of adults; with children, the challenge is to protect their future autonomy.
The American Academy of Pediatrics (AAP) argues that “in most cases, physicians have an ethical (and legal) obligation to obtain parental permission to undertake recommended medical interventions. Physicians should also solicit patient assent when developmentally appropriate.” According to the AAP, elements of assent include:
Helping the patient achieve a developmentally appropriate awareness of her or his condition;
Explaining what the child should expect with tests or treatment;
Assessing the child’s understanding, as well as any pressure to accept treatment;
Soliciting an expression of the child’s willingness to accept care. The AAP notes, however, that “in situations in which the patient will have to receive medical care despite his or her objection, the patient should be told that fact and should not be deceived.”
The benefits of initial therapy for most pediatric cancers are usually sufficient to justify overruling a child’s objection. However, children’s agreement should be sought in circumstances such as relapse with poor prognosis or most experimental therapies where the benefit-risk ratio of treatment is less clear.
Emancipated and Mature Minors
Two legal categories—emancipated and mature minor—give special decision-making status to patients under the age of majority.
Although state laws vary, minors may be emancipated by virtue of either (1) their status as independent from their parents (e.g., living apart, financial self-sufficiency, marriage) or (2) the presence of a specified condition (e.g., sexually transmitted diseases, pregnancy, mental illness). Status-based emancipation is generally justified by the fact that parents no longer have responsibility for the teen, whereas condition-based emancipation is thought to serve the public health by encouraging teens to seek treatment for sensitive conditions. Minors emancipated by virtue of status can generally give or withhold consent in any treatment setting, whereas those with a specified condition can only make independent decisions about the particular condition. An emancipated minor generally has the right to decide who (including her parents) may review her medical record. Although emancipation implies that a minor has legal authority to make his or her own medical decisions, at least in a particular sphere, it does not necessarily follow that the emancipated minor has developed mature judgment. Thus emancipated minors require considerable support and guidance from health care providers as well as from caring adults involved in their lives.
Although state laws vary, minors may be emancipated by virtue of either (1) their status as independent from their parents (e.g., living apart, financial self-sufficiency, marriage) or (2) the presence of a specified condition (e.g., sexually transmitted diseases, pregnancy, mental illness). Status-based emancipation is generally justified by the fact that parents no longer have responsibility for the teen, whereas condition-based emancipation is thought to serve the public health by encouraging teens to seek treatment for sensitive conditions. Minors emancipated by virtue of status can generally give or withhold consent in any treatment setting, whereas those with a specified condition can only make independent decisions about the particular condition. An emancipated minor generally has the right to decide who (including her parents) may review her medical record. Although emancipation implies that a minor has legal authority to make his or her own medical decisions, at least in a particular sphere, it does not necessarily follow that the emancipated minor has developed mature judgment. Thus emancipated minors require considerable support and guidance from health care providers as well as from caring adults involved in their lives.
Many states have case law regarding treatment of mature minors. Although not emancipated, mature minors nevertheless may have a legally enforceable decision-making role based on their capacity to give informed consent. If a minor evidences such capacity in connection with a proposed treatment, including the ability to understand its nature and risks, he or she may have the legal right to consent to or refuse treatment. Even when there is substantial risk, as in a case involving an older adolescent Jehovah’s Witness who declines transfusion, it may be ethically appropriate and legally acceptable to respect the minor’s decision.
Ethical Dilemmas Regarding Informed Consent in Pediatric Oncology
When Parents Do Not Want Their Child to Know the Diagnosis
Cultural norms influence communication of cancer diagnosis and prognosis with patients and families. Early in the medical experience with chemotherapy for childhood cancer, many judged it unethical to inform children with leukemia of their diagnosis, as they needed to be protected from the psychological harms of knowing of their life-threatening illness. By the late 1970s, cultural changes had led to a reversal of this view, with recommendations for full disclosure to adults and disclosure as appropriate to children. It is also not easy to keep secrets when a child comes to a cancer clinic for therapy. Although variability among children and families precludes age-based rules, practical as well as ethical considerations favor disclosing the diagnosis to patients, while working with parents to inform children in a sensitive and individualized manner. It may be helpful to solicit parents’ agreement that children’s direct questions will be answered truthfully and that clinicians will never deliberately lie to the child.
When an Older Child Dissents from Medically Necessary Diagnostic or Therapeutic Procedures
Active dissent, primarily by adolescents, from unwanted treatment poses a particular challenge. Active dissent from research participation is more likely to be respected than dissent from diagnosis or therapy, unless participation in research is likely to bring the child substantial benefit that is not otherwise available.
Although teens lack adults’ nearly unqualified right to refuse medical therapy, parents cannot easily mandate their treatment. There is no simple way to resolve the dilemma that results when adolescents refuse recommended therapy. At a minimum, providers should explore the teen’s capacity, the reasons behind the refusal, how it fits with deeply held values, and the parents’ views. Attempts at persuasion are appropriate. Factors that favor respecting a teen’s refusal include older age, rational reasons for refusal, parental concurrence, and an ambiguous benefit-risk ratio. Assistance from psychosocial clinicians, clergy, ethics committees, or legal counsel should be sought in difficult cases.
Parental Refusal of Therapy on Cultural or Other Grounds
Not all families subscribe to Western allopathic approaches to medicine. Furthermore, alternative approaches to healing are widely employed by patients and families either exclusively or in combination with allopathic treatments. Some parents refuse treatment on cultural, religious, or other grounds. The resulting clashes of cultures tend to be especially dramatic in cases involving children. Should cultural differences be privileged over other reasons for treatment refusal? How can one know when to attribute families’ decisions to culture as opposed to idiosyncratic or even irrational views? One of the hallmarks of good ethical decision making is that similar cases should be decided similarly: if the clinicians would seek a court order to treat a U.S.-born child in similar circumstances, what arguments could justify not seeking a court order for a child from another country?
In many areas of pediatric practice, clinicians have a low threshold for overriding parents’ refusals of prescribed therapy, even when those refusals derive from religious or cultural grounds. When clinicians believe that failure to transfuse will lead to permanent harm, they frequently obtain court orders for blood transfusion against the wishes of parents who are Jehovah’s Witnesses. However, cancer is a chronic disease that is treated over a period of months or years, requiring a long-term therapeutic alliance and adherence to complex regimens. Maintaining a family’s cooperation with core cancer therapy may require concessions to family demands that deviate from optimal medical management but are felt to carry acceptable incremental risk. In many cases, the only alternative is to place the child in foster care for the duration of treatment, with all the family disruption and psychological trauma that this entails.
In cases of treatment refusal, it is important to distinguish among situations in which (1) parents lack decision-making capacity, (2) parents with capacity act on irrational beliefs, and (3) parents act rationally in the service of unusual but deeply held beliefs.23 Because parents have a moral duty to act rationally in their children’s best interests,24 it is easier to challenge or override their decisions in the first two circumstances than in the third.
ETHICS OF RESEARCH INVOLVING HUMAN PARTICIPANTS
Pediatric oncologists are justifiably proud of the remarkable advances in the treatment of childhood cancer during the past five decades. This success can largely be attributed to an extraordinary integration of research with care; when a clinical trial is available, over half of patients take part.25 Given the small numbers and the heterogeneity of childhood cancer, progress would have been much slower without the cooperative trials effort that made it possible.
Despite its achievements, the merging of research and routine care demands caution. As we discuss below, the aims of research and of treatment differ.26 Although it is often possible to achieve both sets of objectives simultaneously, this happy outcome is not automatic. In addition, research with children raises special concerns. Thus pediatric oncology requires attention to and clarity about the complex intersection between clinical research and clinical care.27
A Conceptual Model for Research Involving Human Participants
The distinction between “therapeutic” and “nontherapeutic” research is widely invoked. It featured prominently in the first five
versions of the World Medical Association’s (WMA’s) Declaration of Helsinki, which posited “a fundamental distinction…between medical research in which the aim is essentially diagnostic or therapeutic for a patient, and medical research, the essential object of which is purely scientific…”28 Ethicists, however, have challenged the idea of “research in which the aim is…diagnostic or therapeutic for a patient” as incoherent.29 The WMA abandoned the distinction in the Declaration’s fifth (2000) revision.
versions of the World Medical Association’s (WMA’s) Declaration of Helsinki, which posited “a fundamental distinction…between medical research in which the aim is essentially diagnostic or therapeutic for a patient, and medical research, the essential object of which is purely scientific…”28 Ethicists, however, have challenged the idea of “research in which the aim is…diagnostic or therapeutic for a patient” as incoherent.29 The WMA abandoned the distinction in the Declaration’s fifth (2000) revision.
The Belmont Report offers an alternative conceptual framework.26 Though best known for its principles of respect for persons, beneficence, and justice, the Report’s articulation of the boundary between practice (treatment) and research is equally important. The Report defines practice as “interventions…designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation of success.” In contrast, research is “an activity designed to test a hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge.” The Report thus views research and treatment as conceptually distinct endeavors, albeit ones that may intersect in a trial.
New paradigms in clinical research, including comparative effectiveness research and the learning health care system, prompt conceptual questions for research ethics. There is growing recognition of gaps in evidence regarding optimal treatment, wide variations in patterns of care, quality deficits, and the need for cost-effective use of health care resources. At the same time, health systems and payers routinely capture clinical and administrative data that are invaluable for understanding and improving care. As a result, multiple stakeholders emphasize the need to integrate learning activities, ranging from what has traditionally been called quality improvement to observational and interventional research, into every aspect of care.30,31,32,33 At this level of integration, the boundary between research and treatment inevitably blurs.
The Role of the Clinical Researcher
When a patient enrolls in a trial, the physician-patient relationship changes.34,35 The physician is now also an investigator, and the patient also a study participant. The investigator takes on obligations to science—fidelity to the protocol and its objectives—distinct from her or his fiduciary duties to the patient. This dual obligation requires a unique professionalism. Some have even argued that enrolling in a study—particularly one that involves random assignment—amounts to a renunciation of “personal care,” and is therefore ethically problematic.36,37 This criticism is too strong; pediatric oncology has largely succeeded in aligning the investigator-participant and physician-patient relationships. Nevertheless, the unavoidable tension between these relationships requires recognition,34 and study designs that deviate from a strict conception of the participant’s best interests (e.g., involving extra research-specific bone marrows or lumbar punctures) require rigorous justification. Miller and Rosenstein38 decry the prevalent “therapeutic orientation to clinical trials,” which confounds the roles of clinician and investigator. Joffe and Miller39 call for reconceptualizing the clinical investigator as someone engaged in scientific experimentation, albeit within constraints imposed by the rights and interests of the study participant, rather than as a clinician who also engages in research.
The Therapeutic Misconception and Informed Consent to Research
If research is conceptually distinct from care, then the implications of study enrollment should be clearly disclosed to prospective participants. These include the constraints on individualized care necessitated by the study’s scientific goals and methods and the fact of participation in an endeavor whose primary purpose is to advance knowledge or treatment. Failure to understand this has been termed the “therapeutic misconception,”40 defined by the National Bioethics Advisory Commission (NBAC) as “the belief that the purpose of a clinical trial is to benefit the individual patient rather than to gather data for the purpose of contributing to scientific knowledge.”41 (Importantly, NBAC also emphasized that “[i]t is not a misconception to believe that participants probably will receive good clinical care during research.”) Though the evidence is imperfect, accumulating data suggest that therapeutic misconceptions are prevalent and inhibit participants’ ability to recognize salient distinctions between research and ordinary care.42,43,44 If so, then those who seek informed consent for research must endeavor to counter participants’ tendencies toward therapeutic misconceptions. The American Medical Association (AMA) recommends that, to minimize therapeutic misconceptions as well as perceptions of pressure to enroll, treating physicians should not seek their own patients’ consent to participate in a trial in which they serve as a coinvestigator.45
Kodish et al.43 offer important guidance for investigators who discuss clinical trials with patients and parents. Their model emphasizes the need for a strategic, sequenced approach that focuses first on understanding of a child’s diagnosis and prognosis, followed by discussion of current treatment. Only then should the investigator raise the option of trial participation.46 More generally, available evidence suggests that extended contact with a knowledgeable member of the study team is the most effective means of enhancing participant understanding.47
An Ethical Framework for Clinical Research
Various ethical codes, dating to the Nuremberg Code of 1947, offer guidance for the appropriate conduct of research with human participants. Each provides important new insights, but none offers a comprehensive account. Emanuel et al.48 articulate such a model. Their framework invokes seven principles that facilitate systematic ethical judgments about a study (Table 47.1).
Special Requirements for Research with Children
In addition to the Belmont Report, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research published a separate report on pediatric research.49 The Commission developed the concept of assent (i.e., affirmative agreement). U.S. federal regulations require affirmative agreement from pediatric participants unless either (1) they are incapable of providing meaningful agreement due to age, maturity, or psychological state; or (2) the research offers the prospect of direct benefit that is unavailable outside the research.50 In addition, some children who are developmentally incapable of providing affirmative agreement may still express “deliberate objection.” According to the Commission, such dissent should be respected unless there are compelling reasons to the contrary.
Despite the mandate to obtain the child’s assent, the notion remains challenging. First, it views the child’s decision as radically separate from the parents,’ and therefore ignores the interconnected nature of decision making within families.51 Second, it allows the child to veto the parents’ decision, which some have criticized as failing to respect parents’ appropriate roles. Third, the dichotomous nature of the decision to require or not require assent ignores the nonlinearity of children’s cognitive and moral development,53 and fails to recognize the practical complexities of engaging acutely ill children in these conversations.54 Fourth, there are no agreed-upon standards for what constitutes “meaningful” assent. And finally, while several studies suggest that, under optimal circumstances, children aged 14 years or older can achieve levels of comprehension approaching those of adults, the extent to which younger children can engage in these deliberations is controversial.51,55,56,57 The Children’s Oncology Group (COG) has offered guidance in an effort to fill in these gaps (Table 47.2).58
Although competent individuals can altruistically agree to take part in high-risk research studies without the prospect for compensating benefit, surrogate permission cannot justify enrolling incompetent individuals, including children, in such studies.59 To deal with questions of maximum permissible risk for children, the National Commission defined four categories of pediatric
research. These combine judgments about risk (i.e., minimal risk, minor increment over minimal risk, or more than a minor increment above minimal risk) with determinations about whether the research holds the prospect of direct benefit (Table 47.3). U.S. regulations governing pediatric research incorporate this framework.50 The regulations define minimal-risk research as research in which “the probability and magnitude of harm or discomfort…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,” but do not specify what constitutes a minor increment over minimal risk.60
research. These combine judgments about risk (i.e., minimal risk, minor increment over minimal risk, or more than a minor increment above minimal risk) with determinations about whether the research holds the prospect of direct benefit (Table 47.3). U.S. regulations governing pediatric research incorporate this framework.50 The regulations define minimal-risk research as research in which “the probability and magnitude of harm or discomfort…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,” but do not specify what constitutes a minor increment over minimal risk.60
TABLE 47.1 Ethical Principles Guiding the Design and Conduct of Human Subjects Research57 | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
TABLE 47.2 Children’s Oncology Group Recommendations Regarding Children’s Participation in Research Decisions68 | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Although this framework serves reasonably well, three important problems bear mention. First, the validity and consistency of judgments about the level of risk associated with a particular procedure are questionable.61,62 Second, the standard therapies that patients receive outside trials often entail substantial risk. Many trials include such standard therapies in their treatment backbones, either in the context of testing a novel regimen against a widely
accepted control or—in the setting of comparative effectiveness research—evaluating accepted regimens against each other to determine which is best. From an ethical standpoint, these standard-care risks, to which patients will be exposed whether or not they enter the trial, should not be considered risks of research. Rather, risk evaluation should focus on the incremental risks that patients incur by virtue of their joining the trial.63,64 Finally, the framework presupposes that each study fits uniquely into one of the four categories. However, many protocols involve multiple elements. A trial might both administer an investigational agent that offers the prospect of direct benefit and require serial bone marrow aspirates performed for research purposes. Judging such a protocol as a whole, rather than in terms of its parts, succumbs to the “fallacy of the package deal.”65 Each component should be evaluated individually,51 and investigators should avoid using the benefits of one element (e.g., access to an investigational agent) to justify the burdens of another (e.g., protocol bone marrows).
accepted control or—in the setting of comparative effectiveness research—evaluating accepted regimens against each other to determine which is best. From an ethical standpoint, these standard-care risks, to which patients will be exposed whether or not they enter the trial, should not be considered risks of research. Rather, risk evaluation should focus on the incremental risks that patients incur by virtue of their joining the trial.63,64 Finally, the framework presupposes that each study fits uniquely into one of the four categories. However, many protocols involve multiple elements. A trial might both administer an investigational agent that offers the prospect of direct benefit and require serial bone marrow aspirates performed for research purposes. Judging such a protocol as a whole, rather than in terms of its parts, succumbs to the “fallacy of the package deal.”65 Each component should be evaluated individually,51 and investigators should avoid using the benefits of one element (e.g., access to an investigational agent) to justify the burdens of another (e.g., protocol bone marrows).
TABLE 47.3 Four Categories of Pediatric Research, as Defined in U.S. Federal Regulations59 | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
In 2004, the U.S. Institute of Medicine (IOM) comprehensively reviewed the ethical and regulatory issues related to children’s participation in research.51 The IOM’s report included recommendations addressing definitions of risk thresholds and the relationship of risk to the condition and age of the patient; the need for institutional review board (IRB) review to consider the details of parental permission and assent, with emphasis on process rather than on forms; the need for parental education regarding the research process to facilitate parents’ role as their children’s trustees; and the training of investigators.
Applications
Randomized Trials
At first blush, participation in a randomized controlled trial (RCT), in which individuals are assigned by chance to a control or an experimental arm, seems incompatible with the physician’s fiduciary responsibility to the patient. The most common defense of such trials holds that random assignment is ethical so long as a respected subgroup within the expert medical community prefers each treatment—a state of affairs that has come to be known as “clinical equipoise.”66
The concept of clinical equipoise fails, however, to resolve completely the conflict between the clinician and investigator roles. First, it assumes that because of uncertainty within the medical community regarding optimal treatment, patients will accept having their therapy determined by a flip of the coin. Rather, patients generally expect physicians to integrate consensus views and available evidence with personal experience and “clinical judgment.”
Second, just because equipoise may exist within the medical community, patients may not be indifferent about which treatment they receive.67 Consider a trial evaluating chemotherapy with or without radiotherapy for low-stage Hodgkin disease. Even if oncologists are uncertain which treatment offers the best outcomes, patients or parents may have strong preferences based on such factors as short- and long-term sequelae.
Third, when early-phase trials of novel treatments for cancers with poor prognoses appear promising, families (and oncologists) may rapidly come to prefer the new treatment on the basis of limited and preliminary evidence. It will be difficult to maintain equipoise long enough to generate the evidence needed for clinical, drug approval, and coverage decisions.68
Finally, clinical trials generally are designed to terminate when one treatment proves superior to the other according to some predetermined threshold. Yet, before this threshold is reached, a trend favoring the superior treatment will emerge. Interim data are routinely sequestered, in part because the information could affect willingness to enroll or continue in the trial and thereby threaten study completion. Most RCTs have data monitoring committees and predefined stopping rules to address these tensions, but the optimum procedures and rules for early termination are contested.69,70 The need to withhold interim data concedes that some trials must continue beyond the point at which, were the data known, equipoise would be disturbed.
Some ethicists reject the requirement for equipoise.35,68 Miller and Brody35 argue that equipoise mistakenly judges research according to criteria appropriate to individualized care. In their view, equipoise need not obtain for a study to be ethical, so long as the
trial is not exploitative when assessed according to criteria appropriate to research.48
trial is not exploitative when assessed according to criteria appropriate to research.48
Phase I Trials
Pediatric phase I trials seek to “define a safe and appropriate dose and schedule for new agents that can subsequently be used in phase II trials to test for activity against specific childhood malignancies.”71 They also provide preliminary information about toxicity and pharmacokinetics. They do not seek primarily to evaluate efficacy.
In a classic phase I trial, initial participants receive a low dose of a new agent that is unlikely to be either beneficial or toxic. Doses are increased in successive cohorts until a specified number of participants experience dose-limiting toxicity (DLT). The dose level just below this threshold—the maximum tolerated dose (MTD)—is taken forward into phase II trials.
Phase I trials in pediatric oncology are necessary because MTDs for children and adults often differ. Unless an agent is specific for a particular childhood cancer, pediatric trials typically begin only after the adult MTD is known. This policy reflects a desire to minimize the risks and maximize the benefits of phase I trials for children, but entails some delay in evaluating new agents for pediatric cancer. The starting dose is generally just below the adult MTD, thereby minimizing the number of children who receive suboptimal doses.71
Phase I trials, especially in children, are ethically controversial.72,73,74,75,76,77,78 Objections center on the low likelihood of direct benefit to participants in the face of what is perceived to be substantial risk, the fact that primary end points relate to safety rather than to efficacy, and the challenges of informed decision making for terminally ill patients or their parents.
There is room for disagreement about how favorable or unfavorable the risk-benefit ratio of pediatric phase I trials is. Complete and partial response rates, which range from 6.8% among single-agent trials to 20.1% among multiagent trials,79 are higher than those seen in adult trials.80,81 However, responses are generally short-lived, with a median duration in one study of 60 days.82 Toxic deaths in pediatric trials are uncommon, occurring in 0.5% of participants.79
Given that pediatric phase I trials involve more than a minor increment over minimal risk, can IRBs approve them under U.S. regulations? To do so, IRBs must determine that (1) they offer a prospect for direct benefit, (2) the risks are justified by the anticipated benefits to participants, and (3) the relation of benefits to risks is at least as favorable as that of available alternatives (Table 47.3).50 A crucial question is what the alternatives are for purposes of comparative risk-benefit assessment.77 In our view, unless in a particular case an available alternative offers a more favorable benefit-risk balance, IRBs can approve well-designed phase I trials.
Concerns about informed consent center on the potential desperation of patients or their parents, and on evidence suggesting that participants overestimate benefits and misunderstand how design constraints intersect with therapeutic considerations.74,83 Participants generally enroll for reasons of personal benefit, and few understand that the primary objectives of phase I trials address toxicity and dose finding rather than efficacy.83,84 Furthermore, many participants overestimate the magnitude of expected benefit; in an adult study, respondents on average estimated a 65% likelihood that the phase I agent would “control their cancer.”76
It is important to know whether participants’ misunderstandings derive in part from inaccurate disclosures by investigators. One pediatric study, involving audiotaping of consent conferences, suggested that many investigators fail to describe such critical aspects such as dose finding, dose escalation, or the goal of the trial.84 A review of consent forms showed that most explained the research nature of the trial, the fact that it was designed to evaluate safety or appropriate dose, and the possibility of serious or life-threatening harms.73 However, few clearly distinguished clinical from research procedures, and virtually all made unqualified references to the study agent as “therapy,” thereby perhaps fostering therapeutic misconceptions.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
