This case discusses issues related to the testing of pharmacologic agents in children specifically problems associated with inadequate studies in children and concerns with designing trials involving the pediatric population.
Cureall, a pharmaceutical company, markets the antiviral compound, Eradovir, the first choice therapeutic for the treatment of adult AIDS patients. Eradovir has been shown to increase the life expectancy of certain AIDS patients. It is well known to Cureall scientists that many pediatricians use Eradovir for pediatric AIDS cases, although no clinical studies have evaluated the safety and efficacy of this agent, or any other antiviral agent, in children with AIDS.
Representatives of the American Academy of Pediatrics have been pleading with Cureall executives to begin pediatric clinical trials for Eradovir. The pediatricians explain that adult drug responses do not necessarily extrapolate to children due to their differing physiology. Pediatricians are currently forced to prescribe antivirals to children with AIDS without knowing whether they are safe and/or effective in the pediatric population.
Cureall has agreed to pursue the studies and is developing a study protocol. The overall study design involves initial investigation to determine the appropriate dose of Eradovir to use in a long-term therapeutic trial. The study will compare Eradovir with a placebo. The study has been limited to children 2-12 years of age, but is not confined to certain stages of disease progression. Patients' families or guardians will be compensated for participation by receiving free medical checkups for the subjects during the study, $100 for every month of participation and reimbursement for incurred costs. The company has made appropriate arrangements with four large, urban children's hospitals, chosen on the basis of their large pediatric AIDS caseloads.
A meeting of Cureall scientists for the preparation of the final clinical protocol has sparked debate on the following issues: 1) Is it justified to include an inactive placebo arm to this study? 2) Is the compensation for this study appropriate? 3) Should the payment go to the parent/guardian or child?
Nine months have passed, and all four participating institutions have approved the protocol.
Mary T. is foster mother of Liz, a 3-year-old child who contracted HIV from her mother in utero. Liz's mother has since died from AIDS. Mary and Liz are at the pediatrician's office at Hospital A, one of the four clinical centers participating in the Eradovir children's clinical study. The pediatrician, Dr. Kid, has informed Mary T. of the clinical trial involving Eradovir. The doctor feels that Liz would be a perfect candidate for the study. In keeping with federal guidelines, Dr. Kid goes over the patient consent form with Mary. The consent form details, in lay person's terminology, what the study is investigating and the potential risks and benefits associated with it. Dr. Kid notices that Mary is most concerned with the part of the consent form stating that Eradovir might cause severe kidney, pancreas and gastrointestinal problems. The kidney problems could be fatal in rare cases. Dr. Kid is quick to reassure Mary that this is an extremely rare occurrence, one that he has never witnessed in any of his patients, nor is likely ever to see. Dr. Kid highlights the potential benefits for Liz - a longer life and improved quality of life. In addition, the close medical attention that is part of the protocol will ensure that Liz's progress is closely monitored. Mary decides to sign the consent form and allows Liz to be a study subject in the Eradovir trial.
- Do you think it was appropriate for Dr. Kid to reassure Mary about the potentially serious side effects? Could this be considered coercive behavior on Dr. Kid's part?
- Mary is Liz's foster mother. Do you think her decision was"easier" to make since Liz was not her biological child? Should Dr. Kid have taken the foster relationship into consideration when approaching Mary about Liz's participation in the study?
- If Liz were a 10-year-old child, should she be asked her opinion regarding trial participation?
- If 3-year-old Liz were your biological child, would you let her participate in this trial? Why? Why not?
Brian Schrag, ed., Research Ethics: Cases and Commentaries, Volume 3, Bloomington, Indiana: Association for Practical and Professional Ethics, 1999.
This case is meant to bring to the forefront some issues related to the testing of pharmacologic agents in children. As is stated in the case, children physiologically are not always just smaller versions of adults. Disease states may present and progress differently in children than in adult counterparts. For these reasons, not all therapeutic drugs can be given to children in smaller dosage with the assumption that the pharmacological effects will be the same as in adults. A drug may be more or less efficacious in children than in adults, and the side effect profile may be different or less tolerable to a younger person. These issues can be resolved only by controlled clinical trials in the target population.
Part 1 of this case focuses on the problems associated with inadequate studies in children and concerns with designing trials involving the pediatric population. The first ethical concern is raised by pediatricians using Eradovir in children although the drug has Food and Drug Administration approval only for adult use. This kind of prescribing practice is known as "off-label usage." A pediatrician may be faced with this prescribing situation if the drug of choice has not been studied in children for a specific disease state. Prescribing drugs in children without adequate clinical studies could be detrimental to the patient; however, it also may be extremely beneficial, especially in life-threatening diseases such as AIDS. The agents used to treat AIDS can be very toxic but, given in proper dosages, they can prolong life. Without adequate study, pediatricians may not have information regarding appropriate dosages and therefore can over- or under-medicate the child, increasing risk. On the other hand, patients may be denied potentially life-saving drugs because rigorous tests have not been performed on their specific age group.
Part 1 also deals with protocol design. Cureall scientists are debating the justification of a placebo arm to the trial. For a clinical study to determine whether a therapeutic agent has activity against a specific disease, a control group is needed for comparison of the positive and negative effects of the drug. The control group subjects may be given an inert pill known as a placebo, or, if other drugs are available for use in that disease, the test drug may be compared against the currently used agent, called "standard of care." The problem in this case is that there have been no previous clinical trials with antivirals for AIDS in children, and thus no appropriate therapeutic standard of care has been established. Therefore, Eradovir will need to be tested against a placebo to determine whether it is efficacious. A placebo group in the clinical trial will require that some infected children be given an inactive pill. If Eradovir proves to be effective against AIDS, then the children who received placebo will lose essential treatment time; however, if Eradovir is shown to have untoward effects or to be of little benefit, children in the placebo group will have been spared the risk. American Academy of Pediatrics (AAP) guidelines state that a placebo is ethical to use "when there is no commonly accepted therapy for the condition and the agent under study is the first one that may modify the course of the disease process." (American Academy of Pediatrics, 1995a). In the situation described in this case, a placebo group may be ethically and scientifically justified.
The second question Cureall scientists are discussing is whether compensation of study subjects is appropriate. Subjects in many clinical studies receive a small amount of money or gift certificate as compensation for participating. Ethical issues can arise if the amount paid is so high that it may entice people to take risks they would not normally take for the sake of the financial reward. In the Eradovir study, $100 will be given for every month of study completed in addition to free medical checkups. Since the clinical centers that will be conducting the study are urban hospitals, there is a great chance of having a large percentage of subjects from low-income backgrounds. The study design must guard against parents deciding to enroll their child, regardless of the potential risks associated with Eradovir, for the $100 per month and free medical care. An extra $100 per month may not appear to be a large sum of money, but it may be significant for disadvantaged families. Compensation for any study must be carefully evaluated to minimize the risk of subjects enrolling for financial gain regardless of the risks associated with the study.
In addition to determining participants' compensation, the investigators must decide whether the money will go directly to the child or to the parent/guardian. Is it the child's money or the adult's? The parent or guardian is the one providing the overall care for the child and is responsible for getting the child to the physician's office for study participation. They are taking time out of their schedule and could be taking time from work. However, the child's body is the one being used to conduct the experiment. It seems more ethically appropriate for payment to go directly to the child than to the parent/guardian. Of course, writing a check in the child's name will not guarantee that the child will receive the money. Also, to most children mature enough to understand the value of money, $100 is not a trivial amount. Such issues need to be carefully evaluated while developing the protocol.
The case continues with Part 2, describing a scene in a physician's office with a foster mother (Mary), the foster child who has AIDS (Liz) and the physician (Dr. Kid). Dr. Kid, an investigator involved with Cureall's Eradovir protocol, is trying to recruit Liz as a study subject. The first ethical issue is addressed by Question 1: Dr. Kid reassures Mary about Eradovir's potentially serious, even fatal, side effects. Could Dr. Kid's comments be considered coercion? Dr. Kid's responsibilities are to answer accurately all of Mary's questions and concerns regarding the protocol. Although Dr. Kid is correct in telling Mary that the fatal side effects are rare and that none of his patients has ever suffered from them, it is inappropriate to tell her that he is unlikely ever to witness such adverse events in his patients. Dr. Kid has no way to determine if one of his patients will suffer such problems from Eradovir therapy in the future. After downplaying the negative effects, Dr. Kid highlights all the potential benefits of therapy. His behavior would be considered coercive. Dr. Kid should be honest in telling Mary that Liz could develop a serious and potentially fatal complication, no matter how rare. Further, quickly refocusing Mary on the potential benefits of being a patient in the study is a way of enticing her.
This case is made more complex by Mary being Liz's foster mother rather than her biological parent. Whether or not a foster parent can enroll a foster child in a trial depends on the laws of that particular state (Levine, 1991). Unfortunately, children may be orphaned by AIDS. We will assume that this case is taking place in a state that allows foster children to be enrolled in clinical studies.
Question 2 focuses on Mary's decision to allow Liz's participation and whether the decision is easier to make since she is not a biological parent. That is a very difficult issue to address. Mary, like most foster parents, may be as loving to Liz as she is or would be with her biological children. Just because a child is not a biological offspring does not mean that a foster parent cannot provide as good or possibly better care than the biological parent. Both biological and foster parents are capable of providing loving and nurturing environments; however, both groups can provide unhealthy environments as well. It is unfair to assume that Mary is not giving Liz a wonderful home.
Dr. Kid's role here is to evaluate the relationship between Liz and Mary and to try and determine if it is adequate. He definitely needs to take the foster relationship into consideration. How long has Mary been Liz's foster mother? Does Liz appear happy with Mary? Does Mary have a history of providing foster care and, if so, is it a good record? Does Mary have biological children, and, if so, were/are they well cared for? As with all families he encounters, Dr. Kid needs to evaluate how the parent views the child. The child needs to be protected against enrollment in the study for inappropriate reasons (i.e., financial/medical incentives).
Question 3 raises the issue of assent. In the case, Liz is a 3-year-old child and thus too young to intellectually assess the situation and the associated risks and benefits. Typically, assent is sought from children who have an intellectual age of at least 7 years, in addition to parental permission (American Academy of Pediatrics, 1995b). If Liz were a 10-year-old of normal mental capacity, assent should be required for her participation in the study. If she were to decline enrollment it would be unethical to use coercive measures, financial or otherwise, to induce her to participate.
In Question 4, readers are asked to reflect on whether they would allow their own children to enroll in the Eradovir study. Most people would probably agree that there is good medical and scientific reason to study pharmacologic agents in children. However, whose children should be study subjects? If Liz were your offspring, would you allow her to participate in this clinical study knowing she will exposed to the risk of developing severe and possibly fatal side effects? On the other hand, the therapy may extend her life and improve her quality of life. This question really is posed to get the reader to think more personally about research in children. It may seem necessary, as long as the studies do not involve their children.
This case touches on only a few of the ethical issues related to children's participation in research. As difficult as the concerns may be, the knowledge gained from such studies is worth the effort. Carefully devised research protocols aimed at answering questions regarding children's health will allow for better treatment of pediatric populations, but they must guard against unnecessary risk.
This case raises several of the toughest issues in research ethics. Part 1 focuses on issues that arise in the design of the research project, and Part 2 focuses on issues that arise in the implementation of the study. The questions at the end of Part 1 point to the general ethical dilemma posed by all research using placebos: the role of compensation in research (What is an appropriate amount of compensation?) and the question whether children or their parent/guardian should receive compensation for the child's participation. The first question raised at the end of Part 2 has to do with the appropriate response of the individual who is serving both as a researcher and a clinical doctor to a child who is a potential subject for the study. The last questions point to difficulties in determining the age at which a children can consent for themselves and the subtleties of representative consent, in this case consent for the child by someone other than a biological parent. I don't think I can "answer" these questions; I hope only to articulate what is at issue and why the issues are morally problematic.
Several of the ethical dilemmas posed in this case are not specific to research on children; they arise, as well, in research involving fully competent adults. In this case, the ethical issues are made even more complex and difficult because of the involvement of a child. Moreover, in most research involving children, the child is represented by a parent, but in this case there is further complexity because the child is represented by a guardian, a foster parent.
Let me first consider the issues that would be raised even if no children or representatives were involved. When, if ever, placebo studies are justified is one such issue. Drug tests are morally problematic because they put participants at risk. Since the effects of the drug are not known, there is risk of adverse effects. Indeed, independent of the use of placebos, all researchers have to ask whether the knowledge they will gain is worth the risk to which they expose their research subjects. It is for this reason that poorly designed research is unethical; it puts individuals at risk with little likelihood that good will come from it.
In this context, research involving placebos might be seen as morally preferable to other research because half the subjects will not, in fact, be put at risk. The problem is that in most placebo studies, the drug or therapy being tested is thought to have a positive effect, and yet those receiving the placebo have no chance of receiving this benefit. They are, in effect, being used to prove a point. Of course, it might be argued that this practice is morally neutral since those who receive the placebo are neither being benefited nor put at risk. But this argument is problematic too. The participant's life expectancy might be increased by receiving the experimental drug, or, worse, the subject may be denied a known but moderately effective drug in order to prove the greater effectiveness of the new drug. In cases where a known or moderately effective drug is going to be denied to a participant, or where there is some evidence of a positive effect from the drug to be tested, it would seem that placebo studies have a heavier burden of justification. The value of the knowledge to be obtained must be great enough to overcome the potential harm to the subjects who will not receive positive treatment.
Another issue that arises independent of the involvement of children surrounds the doctor's quick dismissal of Mary's concerns about the risks of participation in the study. That is, even if Mary weren't representing Liz but were herself considering participation in research, the doctor's response to her concerns about the risks would be disturbing. Generally it is recognized that consent to participate in an experiment is valid only when the person is informed and not coerced. To be informed means, among other things, to understand the risks involved; not to be coerced means to freely choose to participate. The latter entails at a minimum that the person has not been threatened with negative consequences for refusal to participate. In this case, the doctor did not threaten Mary, nor did he misinform her. Rather, there is a subtle problem here because Dr. Kid is both the doctor and part of the research team. In relation to Mary, Dr. Kid is an expert, and Mary has put Liz in his hands. In order to ensure that Liz will get good treatment, Mary will want to maintain a good relationship with Dr. Kid. One can't help but wonder if this situation doesn't pressure Mary to agree to Liz's participation in the study. And, while there is no doubt that Dr. Kid is more knowledgeable than Mary, it is not clear that he has the expertise to determine whether participation is a reasonable risk for Liz. Indeed, the fact that he is committed to finding subjects for the study seems to disqualify him from deciding whether Liz should participate. He has a bias in favor of participation. So, while the doctor should discuss the consent form with Mary, he should take care not to let his interest in the study sway her.
Also related to the matter of a valid consent is the question of the appropriate level, if any, of compensation for participation in the study. As already mentioned, one of the criteria for valid consent is that the consent not be coerced. There should be no threat of negative consequences for refusal to participate. This case raises the more subtle issue of whether the promise of compensation might also undermine a valid consent. In other words, the ideal is that individuals freely consent. We can imagine types of compensation that exploit the vulnerabilities of individuals or groups of individuals. If we allow researchers to pay subjects large amounts of money for participation, we are likely to find that poor people will readily participate. But the larger the compensation, the more it will seem that poor people are being exploited. High levels of compensation for participation take advantage of the subjects' circumstances and entice them into doing something they would prefer not to do if their circumstances were better.
So much for the issues that are independent of the involvement of a child. As noted earlier, the issues in this case are compounded by the fact that the potential subject of the research is a child - a child represented by a foster mother, not a biological mother. Children are considered a special class of research subjects because they are thought to be incapable, themselves, of giving a valid consent. They do not have the capacities and experience essential for giving a valid consent. On the other hand, children's bodies differ significantly from adult bodies. So, if research is not done on children, knowledge of how to treat or prevent their illnesses may never be acquired. The point is nicely illustrated in this case insofar as it focuses on study of a drug, Eradovir, which is known to be effective in adults, but has not been tested for treatment of pediatric AIDS. The only way to find out how Eradovir affects pediatric AIDS is to do a study.
If studies are to be done involving children and if children are not capable of giving a valid consent, then the next best thing would seem to be to have parents consent on behalf of their children. Parents, it appears, are more likely than anyone else to understand the best interests of their children. The questions at the end of Part 2 raise two issues about representative consent. The first has to do with whether a foster mother can adequately represent the interests of a child, and the second question has to do with whether the child can or should be involved in the decision to participate.
Both issues are extremely important but both seem to be difficult to deal with in general terms. From a public policy point of view, it seems reasonable: 1) to allow some research on children to be done; 2) not to allow children to consent themselves, unless they have reached a certain age or demonstrated the ability to understand the risks involved; and 3) to assign a representative to represent the best interests of the child when parents cannot do so. I admit that the age at which a child has the ability to represent him- or herself varies from child to child. The law draws a somewhat arbitrary line about the age at which children are old enough to make decisions for themselves, but a line has to be drawn for the protection children. In any case, it is a good thing for the child to be involved in the decision making about participation both because it is likely to help with participation and because it will help the child develop into an adult.
The question whether the foster mother can adequately represent the best interests of the child can be answered in a similar way. It would be unrealistic to claim that foster parents will always act in the best interests of their children, but it is important to remember that it would also be unrealistic to claim that biological parents will always act in the best interests of their children. In reality, there is a good deal of variation among foster parents as well as biological parents. Indeed, it is difficult to say what a parent or a foster parent ought to do in this case.
Author: Deborah G. Johnson, Georgia Institute of Technology.