Ethical Issues in Immunotherapies and Depot Medications for Substance Abuse
Thomas H. Murray
The Hastings Center, Garrison, New York
Soon it may be possible to treat an overdose of phencyclidine (PCP) with a kind of passive immunotherapy, a monoclonal antibody (mAB) specifically engineered to neutralize the effects of PCP. It is passive in the sense that instead of stimulating an individual’s immune system and waiting for it to produce its own antibodies, as traditional vaccines do, mAB therapy provides ready-made antibodies. Monoclonal antibody therapy for PCP overdose is in development. But it represents only one modality among several targeted for one specific problem—overdoses—associated with substance abuse. Other uses are being contemplated. To get a better grasp of the range of potential new interventions and their uses, consider the following hypothetical case.
Imagine a young professional woman, in her mid-20s perhaps, concerned about the use of so-called date-rape drugs. She worries that at the parties she occasionally attends on weekends some unscrupulous man might slip such a drug unnoticed into her drink. Then she learns about a new medication—a long-lasting intervention that would protect her against date-rape drugs by physiologically short-circuiting her body’s vulnerability to the drugs. Someone might succeed in getting her to consume such a powerful drug, but she would be immune to its effects. So, safely, she leaves the party for home.
It would be difficult to see this as anything but a good use of one of the developing technologies for interfering with the physiological action of drugs of abuse. The young adult in this story uses the new medication voluntarily, fully informed of its risks and potential benefits, and for a clearly good purpose—to avert what would have been a terrible wrong—
a possible sexual assault that she might otherwise have been rendered powerless to avoid.
In cases real or hypothetical, the facts, explicit or implicit, are important. In this case the young woman is an adult, not an adolescent or a child. That she is a professional implies that she is functionally competent, even perhaps with a sophisticated grasp of the implications of using the new medication. We must make a few additional assumptions about her—for example, that she is not incapacitated with mental illness, nor does she have a cognitive disability that would make questionable her capacity to understand and appreciate the consequences of her choices. That she is free to attend weekend parties implies that she is free in a more general sense—she is neither incarcerated nor institutionalized. Nor for that matter is she likely to be under the active surveillance of the criminal justice system, as might be the case with someone on probation after being convicted of illegal drug use. There is no reason to suppose that she is addicted to the date-rape drug whose effect she wishes to avoid, so we do not have to consider whether addiction impairs her ability to give free, voluntary, and informed consent. And she is making this decision by and for herself. Neither is she the object of some other person’s would-be benevolence nor is she choosing on someone else’s behalf. Finally, the purpose for which she is using the new medication seems an entirely worthy one. In short, this hypothetical case includes a set of facts that incline us to approve of her decision. In the messier world in which these new medications might be used, the facts will often be murkier and the ethical judgments more complex.
Suppose she was an adolescent or child rather than an adult.
Suppose she had a mental illness or mental disability that interfered with her ability to understand or appreciate what using the new intervention would mean for her.
Suppose she was in prison or a residential drug treatment facility.
Suppose undergoing this treatment was a condition of her parole for substance abuse and she accepted it grudgingly.
Suppose she was powerfully addicted to the drug that the intervention was meant to counteract. Would her consent to treatment mean the same?
Suppose the drug itself was not illegal—that it was alcohol or nicotine rather than some banned substance.
Suppose the intervention was imposed on her by another party: her parents, her employer, the government.
Suppose the intervention was being marketed aggressively, perhaps directly to consumers, by its manufacturer.
Suppose her reason for taking—or being given—the treatment was not to avoid the unequivocal evil of a sexual assault but for a morally ambiguous purpose.
The properties of the interventions themselves are important. For each one, what are its benefits and risks? For how long do its effects persist? For how long can one detect that such an intervention had been attempted (in the case of active immunizations, perhaps a lifetime)? Looking beyond mere physiology, might a treated person’s behavior change in ways that would increase or diminish the risks to his or her own health or to others’ safety and well-being?
To have a clear apprehension of the ethical implications of making available interventions like this, the many likely contexts in which they might be used must be anticipated, not merely the most favorable and ethically unambiguous ones. Also to be considered is how we get from here—where we are currently in terms of our scientific understanding of such interventions, especially their clinical effects—to there. As with all potent new drugs and biologicals, the technologies intended to disarm substances of abuse must undergo a thorough evaluation of their benefits and risks via clinical research. To put it another way, both the ethics of research and the ethics of use must be considered.
After a brief discussion of the intervention technologies themselves and the dimensions of these technologies that are most likely to affect our ethical evaluation of them, this appendix considers first the ethics of research. Along the way what makes informed consent ethically significant and what makes it meaningful in practice are discussed. Then the discussion turns to the ethics of use, focusing on one of the most ethically complex possibilities for use—when parents want to administer these technologies to their children in order to discourage or prevent them from engaging in substance abuse.
FEATURES OF THE POSSIBLE INTERVENTIONS WITH SPECIAL ETHICAL RELEVANCE
Immunotherapies or depot medications might be used for three purposes. The first is to treat an overdose by administering passive immunotherapy in the form of mABs. That is, instead of exposing the immune system to a modified form of the antigen and waiting for the body to mount its own antibody response, passive immunotherapy provides ready-made antibodies. Such a therapy could be life-saving. But like all potent interventions, it will have additional effects. One strategy for helping a person through withdrawal from addiction is to use a modified form
of the drug. The mABs may neutralize such treatments just as effectively as they neutralize the addictive substance, leaving the addict without relief for the symptoms of withdrawal. Another possible danger arises when the person recovers from the overdose but remains in the throes of addiction and may once again seek the drug. As long as the passive immunotherapy is active, the person will need higher doses of the drug in order to achieve the experience that reinforces the addiction. For example, if a person needed to take five times the usual dose to get high from an illegal narcotic, he or she would be exposed to five times as much adulterants or impurities present in the drug.
The second purpose would be to prevent relapse. For this any of the three available modalities might be useful: passive immunotherapy, active immunotherapy, and depot medications. In addition to concerns about the expense of relapse prevention protocols, which would require parallel intensive psychosocial interventions, there will be concerns about the meaningfulness of the person’s informed consent to research or treatment. To the extent that the individual may suffer from a comorbid mental illness, his or her capacity to consent may be impaired. If the relapse prevention protocol is tied in any way to the legal system—as an alternative to incarceration, a condition of probation, or the like—voluntariness is suspect. As an additional observation on active immunotherapies, biological traces, such as persistent antibodies or memory lymphocytes, of active immunotherapy may persist at detectable levels for a very long time, perhaps even a lifetime. This would be true for active immunotherapies used either for relapse prevention or, in the third likely purpose of use, protection protocols.
The desire to protect individuals or populations from substance abuse may prompt the use of protection protocols. Here the analogy with traditional immunotherapies for infectious diseases is at its strongest. Research on such protocols may present significant ethical challenges, but the most difficult problems are likely to arise if and when such products are approved for marketing and when parents seek them for their children.
There is an important observation well known to physicians and others familiar with prescription drug policy in the United States, but probably not broadly understood by the public. Once a drug is approved for marketing in this country, physicians can prescribe it for indications or populations not included in the official Food and Drug Administraion (FDA) approval. Physicians could, for example, take an active immunotherapy approved for relapse prevention in adults and prescribe it for the purpose of “protecting” a young child from becoming addicted to the same substance. Pharmaceutical companies have devised ways to encourage such off-label use.
CHALLENGES IN THE ETHICS OF RESEARCH: FROM IDEA TO PRACTICE
To get from a promising idea to an effective treatment, the immunotherapies and depot medications under consideration must undergo thorough evaluation in clinical research. The ethical challenges posed by clinical research on these particular interventions on the likely populations of interest and at risk are particularly daunting. This section attempts to identify the challenges. Where clear conclusions can be drawn and confident recommendations made, that will be done. But many problems will go unresolved. For these the nature of the problem is described along with the values at stake.
The world of clinical research is itself beset with criticisms these days (Angell, 2000; Bodenheimer, 2000). Substantive matters for concern include the following: Who gets recruited as clinical research subjects and why? What are the ethical implications involved in study design, methodology, and outcome measures? How can informed consent be made to serve in practice the noble ethical purposes it is presumed to serve in theory (see Faden, Beauchamp, and King, 1986)? Less ethically complex forms of clinical research may struggle with subject recruitment, study design, and the like; all forms of clinical research must confront the challenge of making informed consent meaningful (Feussner and Murray, 2002).
Who Will the Subjects of Research Be?
Though there will certainly be overlap, the three purposes of treatment—overdose protocols, relapse prevention, and protection—have features that distinguish them from each other.
Once overdose protocols move into the stage of testing for efficacy, the subjects of research will include, unsurprisingly, individuals who have taken an overdose of a drug of abuse. The clinical state of such individuals may vary considerably as a function of the particular drug taken, the dose, the time elapsed since taken, and their overall health, among other factors. In some cases in which the urgency is low, time is available, and the person is conscious, competent, and communicative, it may be possible to inform the person and get his or her voluntary consent to participate in research. In other instances, however, the person may be confused, incoherent, or unconscious; whatever intervention is to be made must be begun urgently; and the person may be in police custody, transported from an institution, or otherwise unfree.
Informed consent has been the fulcrum of the ethics of research with human subjects at least since the Nuremberg Code. Informed consent performs double duty: It demonstrates respect for the person being asked to participate in research and, by providing an account of the risks and ben-
efits, gives the individual the opportunity to exercise her or his own preferences and hence is believed to promote the most appropriate overall balance of benefit and risk.
Many factors can impair informed consent in practice. Some can be described as subject-specific factors, which can be further subdivided into those factors that affect a person’s capacity and those that affect the person’s voluntariness. In addition, there are factors related to the person requesting consent and the setting—in the broadest sense—in which the consent is being sought.
Subject-specific factors affecting capacity include the ability to understand the information being conveyed (including cognitive capacity, familiarity with the language used, and literacy if printed information is used), the ability to appreciate the significance of that information for the decision to be made, and the likelihood of avoiding the cognitive biases and errors that infect so much decision making (Holmes-Rovner and Wills, 2002; Ubel, 2002).
If a person is severely intoxicated, disoriented, or muddled, his or her capacity to consent is put into question. People with mental disorders interfering with their capacity to understand and appreciate the implications of a decision to enroll in a research protocol may not be able to give a morally meaningful and valid informed consent to research (National Bioethics Advisory Commission, 1998; Appelbaum, 2002). If a person is unconscious (which will be the case for some people for whom overdose protocols are designed), the capacity for consent is, at that time at least, nil. To deal with this last category of persons, those requiring emergency medical treatment while not competent to give consent, a new set of rules has been adopted (61 Federal Register 51, 1996).
New rules were needed to extricate us from an ethical Catch-22. On the one hand, emergency room physicians were permitted, ethically and legally, to try innovative therapies to help their patients, even when patients were unable to give consent. On the other hand, under the rules governing research with human subjects, those physicians were not permitted to do the research necessary to learn whether these new interventions worked better or worse than the old ones, thus the Catch-22. The new rules for research with patients unable to give consent in the emergency room create stringent safeguards to protect such patients against abuse or frivolous experimentation while permitting research on the therapies that might benefit those same patients. One of the safeguards requires seeking and obtaining what is being called “community consent.” The details of community consent are being worked out. Deciding what constitutes adequate community consent for research on persons suffering from drug overdoses will be a challenge. Serious work on that problem should begin immediately.
What to make of the capacity to consent to participate in research when a person is addicted to a substance of abuse is a more complex question (McCrady and Bux, 1999). In general, we do not act as if we believe that addiction relieves people of all moral and legal responsibilities when they do something wrong. Rather, it is assumed that people are accountable for their actions in the absence of convincing reasons to think otherwise. That presumption does not carry over straightforwardly to the context of research. In recruiting people as research participants, especially for anything involving more than minimal risk, the presumption is that they should be informed competent volunteers. Evidence of some impairment of voluntariness or of cognitive capacity can be enough to disqualify someone from enrolling in a research protocol (Nelson and Merz, 2002). Therefore, the fact that someone is addicted may carry more weight in the judgment on whether to permit that person to volunteer for research than it carries in a criminal courtroom.
A recent discussion about consenting to participate in a research study involving prescription medication for heroin argues that the decisional impairments characteristic of heroin addiction, which include compulsion, intoxication, and withdrawal, compromise both understanding and voluntariness (Charland, 2002). But relapse prevention studies are likely to differ from heroin administration studies in important ways. The interventions given in relapse prevention studies may reduce the compulsion, prevent intoxication, and diminish or eliminate the symptoms of withdrawal. The desire to escape from addiction should be distinguished from the addiction itself.
Subject-specific factors affecting voluntariness include being incarcerated, institutionalized, or otherwise under the control or influence of other parties such that one’s liberty to consent or refuse to consent is diminished.
Some substances of abuse are illegal; others, such as alcohol, cause intoxication that can result in entanglement with law enforcement through, for example, driving while impaired or fighting. Many potential research subjects will have had interactions with the criminal justice system (McCrady and Bux, 1999). Some may be in prison; some may be on probation or under some form of surveillance; others may believe they are being offered a choice between being punished or enrolling in research. In all such cases, voluntariness may be in question.
Factors involving the person requesting consent may also pose challenges to obtaining fully voluntary and informed consent for research on immunotherapies and depot medications for substances of abuse. In situations in which a treating physician recommends to a patient that she or he consider enrolling in a clinical trial, the usual issues include concerns about possible conflicts of interest on the physician’s part—for example, if the physician has any financial interest in the drug or device being tested
or has been offered incentives for recruiting research subjects (Bekelman, Li, and Gross, 2003). Such concerns are common to a broad range of research protocols and subject recruitments; they may be pertinent to research on immunotherapies and depot medications for substances of abuse as well. But the person requesting consent for research on these particular interventions may have a more complex relationship with the prospective subject (Chen, Miller, and Rosenstein, 2002).
The requester may be perceived by the prospective subject to be in a position of potentially coercive authority. How did the potential research subject come into contact with the requester? There is no one scenario likely to account for all cases, but it may be instructive to consider plausible cases for the three categories of intervention mentioned earlier: overdose treatments, relapse prevention protocols, and protection protocols.
For prospective research subjects in overdose treatment protocols, some, perhaps most, may be unconscious, intoxicated, or so muddled as a consequence of their overdose that fully informed consent is impossible. Leaving such cases aside, some individuals may present voluntarily for treatment at an emergency room for fear they have taken an overdose. There they may encounter a specialist in emergency medicine who is collaborating in a clinical trial of passive immunotherapy (mABs) to treat an overdose of PCP. In all likelihood they will have no previous relationship with this physician. If the drug ingested is illegal, like PCP, they may fear arrest; if they have a previous record of drug-related crimes, they may be wary of giving any personal information to emergency room staff; indeed, they may give a false name. In the best of cases, they will be truthful about the drug and their own identity and health history; the emergency room physician will explain carefully and thoroughly what the research protocol entails and offer the patient the right to consent or refuse, making it completely clear that the patient will receive appropriate treatment in either case; and the investigators will have taken the permitted steps to protect subjects’ confidentiality, so that enrolling in the clinical trial will not increase their risk of criminal prosecution. Life, of course, does not always present the best of cases.
The possibility of participating in research on relapse prevention protocols presupposes that a prospective subject has experienced addiction to one or more substances of abuse (otherwise it would not be a relapse). The person inquiring about whether a prospective subject would be interested in enrolling in the research may be the individual’s primary care physician. It seems more likely though that the requester specializes in the treatment of substance abuse and hence may work in a substance abuse clinic or resident treatment facility. The physician’s role may be more confrontational, more controlling than the typical primary care doctor; the physician’s role may also include what sociologists call the “dirty
work” of medicine—social control functions such as those performed by occupational physicians who certify whether an employee is fit to return to work or whether an injury was job related (Murray, 1986). The substance abuse clinic physician may hold the power to declare whether a patient is “clean,” if it is safe to release the individual from the facility, or if the individual is complying with the demands of her or his probation. Whenever the physician or someone perceived as that physician’s agent makes the request, the prospective research subject may feel compelled to agree—because of the requester’s power over the person.
Research on protection protocols is likely to come only after the interventions have been vetted in overdose and relapse prevention studies. Only plausible speculation can be offered about the circumstances of protection protocols. In the ethically simplest case, a study of a well-characterized intervention with only a few minor side effects is offered to free competent adults. The “protection” intervention might be a passive immunization with mABs that interfere with the action of date-rape drugs—the example used at the beginning of this chapter. (Designing an ethically acceptable protocol to test the safety and clinical efficacy of such an intervention for this purpose would be a challenge.) Who would conduct such a study? In what institutional settings might it be done? Who would have the interest and the resources to fund such a study? If these questions could be answered satisfactorily, use of such an intervention for such a purpose could be thought of as a version of a “Ulysses contract”; just as Ulysses had his crew bind him to the mast so that he could not yield to the Sirens’ temptation, so a woman immunizing herself against the action of a date-rape drug is trying to protect against yielding to the seductive temptations of the drug (Dresser, 1984).
In practice, it appears much more likely that the principal demand for protection protocols will come from parents anxious to prevent their children from becoming dependent on substances of abuse, whether illegal or legal. This section focuses on the context of research, so the discussion of likely scenarios in which parents might seek such protective interventions for their children is deferred until later in this appendix. The initial research on protection protocols is virtually certain to have competent adults as its first subjects. Enrolling informed adults with full capacity to consent, whose participation is clearly voluntary, simplifies the ethical analysis of such trials. All the usual questions about the ethics of research—the nature and extent of the risks, the possibility of benefit to the subjects and to others, the protections afforded to subjects’ privacy, the absence of troublesome conflicts of interest among the investigators, and so on—will still need to be asked and satisfactorily answered.
Suppose that these initial clinical trials are done and that they confirm that the intervention is relatively safe and effective. If, as seems likely for
many of the interventions imagined, its most likely practical use is in children and adolescents, decisions will need to be made as to whether studies must or should be done with such subjects who are not fully competent or independent and, if so, how those studies should be designed and what will count as ethically adequate consent (from parents or legal guardians) and assent (from the subjects themselves) (Kopelman, 2000; Food and Drug Administration, 2001).
The last topic under the ethics of research is the setting in which potential research subjects are identified, recruited, and enrolled. Of the principal settings in which most clinical research subjects are recruited—the physician’s practice and the specialty clinic or hospital—the former is likely to be less commonly employed for the studies under consideration here, and the latter, in these cases the substance abuse clinic, has properties that place it outside the usual clinic environment, especially the social control aspects of treatment for substance abuse and the fact that much of the conduct creating the need for treatment may be illegal. Other settings include the emergency room (especially for overdose treatment protocols) and the family, for protection protocols used in children and adolescents.
One potential problem lies at the intersection of the patient, the person requesting consent, and the setting; it goes by the name of therapeutic misconception. People being recruited as research subjects for clinical trials often fail to appreciate the difference between medical care and research—a phenomenon dubbed the therapeutic misconception, defined as occurring “when a research subject fails to appreciate the distinction between the imperatives of clinical research and [those] of ordinary treatment, and therefore inaccurately attributes therapeutic intent to research procedures. Most often, this will occur in clinical research, but it can also occur in nonclinical settings” (Lidz and Appelbaum, 2002, V-57). Patients often appear to believe that their physicians would only recommend that they enroll in research when those physicians are convinced that doing so is in the patients’ best interests. The norms that guide clinical care and those that guide research differ in important respects. Good clinical care embodies individualized care; good research requires standardized treatment. Clinical care is aimed at benefiting a single patient; research is aimed at creating generalizable knowledge and benefiting future patients.
There are data to support the existence and significance of the therapeutic misconception. A study published in 1995 reported that 78 percent of Americans did not know what “randomly” meant and 83 percent could not explain “double blind” (Waggoner and Mayo, 1995). In a study of research subjects in four chemotherapy Phase I trials—toxicity and dosage studies—at the National Institutes of Health, all 127 subjects said that the trial had treatment as well as research aims (Schaeffer et al., 1996).
Lidz and Appelbaum (2002) exhort researchers to try to dispel the
therapeutic misconception. They acknowledge that some people may decline to participate in research when they understand fully the difference between standardized research protocols and individualized treatment, but they point to plausible advantages for the research enterprise: fewer angry subjects during and after the conclusion of studies; the possibility of fewer dropouts in the course of studies; and the preservation of public trust in research and researchers, including the willingness to participate as research subjects.
Is the therapeutic misconception a problem for research on immunotherapies and depot medications for substance abuse? If the subjects in these studies are less well educated and less sophisticated about scientific research, they may be more susceptible to the therapeutic misconception. If, on the other hand, they are more suspicious or mistrustful of the health professionals providing their clinical care, they may not presume that the principle of personal care governs their relationship with their clinicians and may be less likely to fall prey to the therapeutic misconception. To the extent that the populations from which subjects are drawn for research are already mistrustful of researchers, the therapeutic misconception and the resentment that may follow once it is corrected may exacerbate those communities’ suspicion of research. This would be a particularly unfortunate outcome for everyone.
CHALLENGES IN THE ETHICS OF USE: FROM IDEAL TO MUNDANE REALITY
It is not difficult to imagine situations in which using an immunotherapy or depot medication would be welcome by the person using it and deemed a good thing by informed observers. The hypothetical case with which this chapter began is an example. The principal virtue of a hypothetical case is, of course, that its creator can load it with whatever details he or she wants to elicit the desired response. But there is an associated trap: Rarely does reality conform to the hypothetical. Life brings heaps of complexity, and people’s judgments, rather than being clear and ringing, are often shadowed by ambiguity and uncertainty. Using depot medications and immunotherapies for substance abuse will be no exception to the rule of complexity and ambiguity.
We may worry more intensely and systematically about informed consent in the context of research, but informed consent is important in treatment as well. This is especially so when there are reasons to fear that the person may lack elements of the capacity to make meaningful and informed decisions or when the voluntariness of a person’s consent may be in doubt. The same characteristics that lead us to worry about the capacity of people to consent to research will also cause concern about the
meaningfulness of their consent to treatment: cognitive and emotional maturity, mental illness and mental disability, addiction. The same situations that lead us to worry about the voluntariness of consent to research will be relevant again in the context of treatment—that a person is incarcerated or under the threat of incarceration, that an individual is under the power of some other person or entity such as a government agency. The fact that many substances of abuse are illegal and that others that are legal may nonetheless be linked to actions that can get someone in trouble with the law (like driving under the influence) adds complexity to the analysis. Finally, there is a certain moralism attached to substance abuse that may affect how health care professionals regard and act toward people seeking treatment for substance abuse (Klerman, 1972). That moralism may incline physicians toward harsher interventions and may make them less sensitive to privacy and confidentiality with such patients.
How significant are these concerns likely to be? Looking again at the three categories of likely treatment protocols reveals important differences among them. First, overdose treatment protocols that use passive immunotherapies raise the fewest red flags. People for whom this is an indicated treatment have either been brought to or presented themselves at an emergency room. If they are conscious and competent, they can consent to the intervention. If they are unconscious or incompetent, the treating physician has a professional ethical obligation to provide appropriate treatment; if passive immunotherapy is proven to be superior to other interventions, the physician is simply fulfilling his or her professional duty by applying it.
This is not to say that passive immunotherapies carry no short- or long-term risks, medical or otherwise. In the example mentioned in the committee’s report, a person treated for an overdose in this way might face some risks for the interval—as long as several months—during which the mABs remained active. If the person experienced withdrawal, one treatment strategy for withdrawal would be rendered more difficult—that is, treatment with an agonist that ameliorates the pangs of withdrawal. The mABs may interfere with the action of the agonist just as it blocks the activity of the substance of abuse. Treating withdrawal then might require much higher doses of the agonist, with whatever risks attend such doses. If the person tries using the drug again while the mABs are still active, he or she will have to use larger doses in order to overcome the antagonistic activity of the mABs. If the drug itself has toxic effects or if as a street drug it contains adulterants, the risks of physical harm increase as the amount used increases. These risks are contingent on the actions of the person treated. Some people may get additional benefits from passive immunotherapy if they choose to forego further substance abuse while the mABs are in their bodies.
On the whole, passive immunotherapy in an overdose treatment protocol raises relatively few novel or difficult ethical problems. Attention will have to be given to follow-up for the interval during which the mABs remain active. But with reasonable attention to informed consent and treatment under emergency circumstances, to patient confidentiality, and to the training of health care professionals to gain perspective on the perils of moralizing, this category of interventions is not especially ethically problematic.
Relapse prevention protocols present a wider spectrum of possible interventions as well as contexts of treatment. Like overdose treatment, passive immunotherapy could be used. Unlike overdose treatment, the therapy would have to follow a period of detoxification and be readministered periodically in conjunction with psychosocial interventions. Depot medications would also require repeated treatment and psychosocial interventions, possibly accompanied by urine testing for compliance. Active immunization is more complicated still. Like the other two categories, it is likely to require multiple administrations (to induce antibody production) and periodic readministration to keep antibody levels up as necessary. In contrast to passive immunotherapy in which the quantity of antibodies administered is known, people’s antibody production in response to active immunization can be highly variable. Also, active immunization may become a kind of “scarlet letter,” leaving lifelong markers of interest to others (e.g., military, police, employer, insurer, even a future spouse).
Beyond the clinical complications, relapse prevention protocols are likely to be given in contexts fraught with ethical complexities. In the discussion of research on such protocols, some of these complexities were mentioned: the reality that the patient has a substance abuse problem and, very possibly, has had or is at risk of encounters with the law; the clinicians treating such patients may have complex relationships with them, including indirect power over their liberty or their eligibility for treatment. Typical sources of power discrepancies between physicians and patients become magnified and may be more numerous in relapse prevention treatments. Differences in education, social class, and institutional power have greater significance when physicians exert control over patients’ destinies in more than a narrowly medical sense.
There may also be times when the physician acts explicitly as an agent of the state. For example, the patient may be given the option of relapse prevention as an alternative to prison, or the patient may be compelled to see the physician for treatment and monitoring as a condition of parole. Of the options available to the patient, this may be the least undesirable. The implications for informed consent, the physician-patient relationship, and the role of the physician are serious and must be given full weight in designing acceptable policies.
Protection protocols have potentially the widest scope for application and also raise the most novel and challenging ethical issues. Again, the hypothetical case that began this paper is an example of a protection protocol that seems, on balance, well justified. Alter the facts of the case, however, and matters may not seem so clear anymore. A less than fully competent or voluntary patient, a dubious ratio of risk to benefit, or uncertainty about long-term effects raise provocative ethical questions. The questions become most urgent and difficult when contemplating a likely—perhaps the most likely—use of protection protocols: parents wishing to have the intervention for their children.
PARENTS, CHILDREN, AND PROTECTION AGAINST SUBSTANCE ABUSE
Parents allow their children to be vaccinated in an effort to prevent them from being harmed by diseases that used to cause widespread suffering and death. Even parents who refuse to have their children vaccinated may be acting from a similar motivation; they may be convinced that the vaccine is a greater risk to their children than the disease itself. Parents in both cases are trying to protect their children from harm. It should be no surprise if and when immunotherapies and depot medications against substances of abuse are approved for marketing that some parents will seek such interventions for their children. Policy makers and clinicians will be called on to anticipate and respond to such requests. Among the factors to be considered are:
Is the substance of abuse itself legal for any population, such as adults (e.g., alcohol, nicotine) or illegal (e.g., opiates, PCP, marijuana)?
What are the risks of the particular intervention?
What is the duration of action of the intervention? Will its effects outlast childhood?
Will the biological evidence that such an intervention was made survive into adulthood and with what medical or social consequences?
Will intervening now foreclose choices when the individual reaches adulthood?
Might there be distinct social patterns to the use of such interventions? Will it be more attractive to people in cities or suburbs? To the relatively wealthy, poor, or middle class? To people with different religious commitments? To people whose insurer will cover the cost?
The one certainty here is that parents will have a vast range of reactions. Some parents, out of conviction, experience, or fear may leap to immunotherapies or depot medications as the best way to ensure that their children do not become addicted to one or more drugs of abuse, from alcohol and nicotine to heroin, cocaine, or other illegal drugs. Other parents, out of caution, skepticism, confidence, or beliefs about their children’s risks, may spurn the interventions. Initially at least, not all parents will know about them. And depending on their cost, some parents may decide they cannot afford immunotherapies or depot medications even if they think the interventions are desirable. Also, lobbying efforts can be expected from those hoping to profit from the sale of immunotherapies and depot medications to encourage or compel insurers to pay for their use.
A remote and unlikely alternative would be a state or federal policy requiring, for example, that all children be immunized against one or more substances of abuse, the way childhood immunizations are required for common infectious diseases. Or perhaps there could be voluntary programs promoting periodic administration of depot medications or active immunotherapies (that require regular reimmunization) on the model of the annual flu shots aimed at vulnerable populations. Such programs would require very different risk-benefit judgments than currently exist; the risks of the interventions would have to be seen to be very low and the benefits fairly clear and certain, while the risks of substance abuse would have to be seen as severe enough to be worth the risk and expense. Unfortunately, drug policy in the United States has at times been shaped more by fear and misinformation than solid science, so the possibility of government initiatives to promote such immunotherapies and depot medications, even in the absence of clear evidence of their wisdom, cannot be dismissed.
Before people begin contemplating using immunotherapies or depot medications as public health measures—coercive or quasi-voluntary—and likely even well before these interventions are tested or approved for use in children, some parents will seek to use them on their children. Similar behavior has occurred, arguably for a much less compelling purpose, with human growth hormone (hGH; Murray, 1987).
Cadaveric hGH was introduced for use in children suffering from deficiencies in physiologically active hGH—either because low levels were produced or because what was produced was biologically inactive. By the early 1980s some parents were seeking hGH for their children who did not have evidence of hGH deficiency and who may—or may not—have been short for their age. That this was happening was confirmed in many ways, including articles in the scholarly literature (Benjamin, Muyskens, and Saenger, 1984) and in one instance a conversation with a
pediatric endocrinologist at an FDA hearing at which this author was asked to testify. (This doctor also said that all or virtually all the requests she had received came from physicians.) Such parental pleas came despite consistent opposition by the Ad Hoc Committee on Growth Hormone Usage (1983) and the American Academy of Pediatrics (1997). At least some physicians gave in to these pleas (Cuttler et al., 1996).
Parents who sought hGH for their non-hGH-deficient children did so, it appears, from a variety of motives. In some cases they may have wanted to spare their children from the social disadvantages, and at times discrimination, visited on adolescents and adults of short stature. Discrimination of this sort has been dubbed “heightism,” like racism, sexism, or ageism—that is, treating or regarding a person according to an attribute that is irrelevant to the matter at hand. The flip side of heightism is exemplified by parents who seek hGH for their children because of the perceived advantages of being taller. These parents, rather than attempting to spare their children from the disadvantages of heightism, instead seek to exploit it for their children’s benefit.
With hGH, parents may be motivated by a desire to help their child overcome a disease (a lack of physiologically active hGH), a disability (severe idiopathic short stature), or a disadvantage (idiopathic short stature that is not severe—e.g., less than two standard deviations from the population average). Some parents have sought a comparative advantage for their children. A pediatric endocrinologist directing the hGH program at a major American academic medical center told me of a teenage girl, 5′9″, whose parents wanted her treated with growth hormone. She played volleyball and her coach had told them that if she were 4 inches taller she would surely be offered a scholarship from any college with a women’s volleyball program.
As it happens, the evidence is mixed that hGH given within a physiologically normal dosage range increases the height of non-hGH-deficient children. Some studies show a slight increase in height; other studies show no difference. The studies are mostly small and typically fail to follow the children into adulthood. The cost of height attained, if any, is estimated at no less than $14,000 per centimeter, or roughly $35,000 per inch—and that assumes the best response found in studies of children with idiopathic short stature on optimized treatment with both hGH and gonadotropin-releasing hormone (Kaplowitz, 2001). It is an enormous financial investment for an uncertain anatomical outcome. Perhaps more important, years’ worth of hGH injections may focus undue attention on a single criterion by which that child literally “comes up short” rather than on the child’s strengths and talents. Whether hGH treatment is on the whole a benefit to a child with idiopathic short stature—where final adult height may be a disadvantage but not a disability—is open to question.
In the case of immunotherapies and depot medications for substances of abuse, parents’ motivations are more likely to reflect a desire to prevent harm to their child rather than to seek a competitive advantage, making it similar to the use of hGH to treat disease or to ameliorate disability. But a child put on a protection protocol does not yet have a disease, as does a child with diagnosable hGH deficiency. The closest analogy then is with children with severe idiopathic short stature. These children have no known disease, but they are at risk of the sort of harm that often faces people of severe short stature; these risks are due mostly to human choices in the construction of our human-made physical environment and to the attitudes, beliefs, and actions of the people they encounter.
When parents have their children put on immunotherapies or depot medications to protect them against substance abuse, the parents here, like the parents of children with severe idiopathic short stature, are attempting to protect their children against what the parents regard as the risk of serious harm. In both cases, parents may perceive their children as being vulnerable. But the vulnerabilities are different. Children with severe short stature are vulnerable precisely because in this respect they are unlike other children of similar age and circumstances. Children enrolled in protection protocols are vulnerable precisely because they are like other children; their lack of maturity and wisdom, their susceptibility to peer pressure, the propensity of young people to experiment are all attributes that are widely shared.
Another factor distinguishing children in the two cases is the likelihood of harm. Children with severe short stature will suffer harms associated with disability; the question is only how often and how deleteriously. Parents do have nonmedical options for helping their children. They can build their child’s sense of self-worth, emphasize the child’s strengths, and find communities that welcome their child. Society can also become more accommodating to differences and less prone to the prejudice of heightism. But however resourceful and strong parents may be, children with severe short stature will likely be exposed to some types of harm, some of the time.
Children placed on protection protocols may have no elevated risk of harm from substance abuse. Merely being a child or adolescent does not mean that an individual will suffer the harms associated with substance abuse. Some children avoid abuse altogether; others experiment briefly but either cease such use completely or in time adopt a pattern of use of, for example, alcohol, that is mature and controlled. The benefits of protection protocols are, therefore, less certain in the degree that the harms are also less certain.
A broad range of plausible scenarios can be imagined in which parents
seek immunotherapies or depot medications for their children. In the hypothetical case with which this appendix began, we need only make the young woman an adolescent and have the decision made by her parents. Physicians may face ethical challenges in such cases depending on the age of the child or adolescent, their child’s acceptance or resistance to the parents’ wishes, and the intervention’s duration of action. Suppose that parents present for protection a relatively young child. The younger the child, the more willing society is to accept the parents’ authority to make medical decisions on the child’s behalf. Suppose the child does not want the intervention. When may an intervention be imposed on a child against her or his will? Suppose that the intervention lasts for months, years, decades, or even a lifetime. Should we be less quick to apply such interventions when the consequences for the child are long lasting?
In a study of the issues raised by enhancement via gene transfer, Juengst distinguishes among three types of control: personal, professional, and policy. “Personal” refers to the decisions made by individuals or, in the case of children, by their parents. These decisions are shaped by individual moral beliefs and broad cultural forces. “Professional” refers to the standards, formal or informal, that govern the practices of professionals. The American Academy of Pediatrics and Lawson-Wilkens Endocrine Society’s guidelines for using hGH in children are examples of professional standards that regulate practices in the absence of governmental laws or regulations (Lawson Wilkins Pediatric Endocrine Society, 1995; American Academy of Pediatrics Committee on Drugs and Committee on Bioethics, 1997). Professional standards can be quite effective if they are clear and widely respected. However, even if a consensus is formed among physicians to strictly limit access to immunotherapies and depot medications for substance abuse, some physicians might, out of fear of drug dependency or because of sentiments strongly in favor of parental discretion, accede to parental requests for such access. Control by “policy” refers to formal governmental actions whether by legislation or regulation.
It seems plausible that immunotherapies and depot medications will at least initially be available only by prescription. Anyone seeking these interventions through legally approved sources, then, will presumably consult a physician or other professional entitled by law to prescribe them. What will parents request and what should clinicians do in response? What public policies should there be to cope with these interventions? Consider two scenarios. In the first, parents ask a physician to prescribe a depot medication for nicotine addiction for their 12-year-old child. In the second, parents ask that a new very long-lasting vaccine—an active immunotherapy—against response to opiates be administered to their 15-year-old child.
DEPOT THERAPY AGAINST NICOTINE ADDICTION
The savvy parents of 12-year-old Vicky understand—almost as well as the tobacco companies—that people who do not begin smoking cigarettes during adolescence or childhood rarely become addicted to nicotine. Vicky’s parents also understand the power of peer pressure at the relatively affluent school their daughter attends. Vicky has not given her parents any particular reason to worry, but she is a bit shy and terribly eager to please her fellow students in the hope that they will become her friends. Some of Vicky’s classmates are experimenting with smoking as a form of adolescent rebellion and because they believe it gives them an aura of maturity. Vicky’s parents are worried that she might take up smoking as a way of ingratiating herself with the “popular” clique at school. Though they recognize that it will not affect Vicky’s underlying desires for acceptance, they ask her pediatrician for a prescription for the new depot medication against nicotine for their daughter.
A VACCINE AGAINST OPIATE ADDICTION
Larry’s parents are worried that their 15-year-old son will fall prey to the heroin dealers that infest their neighborhood. So far, they believe, he has stayed clean. But the children of three friends have become addicts and one has died of an overdose. Recently, a vaccine against opiates was approved by the FDA. It is an active vaccine that spurs the body to produce antibodies, some of which are likely to be detectable for many years. There is uncertainty about just how long the immunological effect will linger. This particular vaccine works very well and seems to provide long-lasting protection, but to be safe the current recommendation is to have periodic booster shots.
CHALLENGES TO PARENTS, HEALTH CARE PROFESSIONS, AND PUBLIC POLICY
What would a good and responsible parent do with respect to depot medications or immunotherapies for substances of abuse? This is not a simple question, and it does not invite easy answers. People who think that they know the right answer are likely to be confronted by other people equally certain that they know the right—and precisely opposite—answer.
The Worth of a Child (Murray, 1996) proposes an understanding of the relationship between parents and children in which each depends on the other for the conditions necessary for their individual and mutual flourishing. Actions, practices, policies, and laws are defensible to the degree to which they create or support conditions conducive to the family flourishing and to the values central to family life—both those values intrinsic to
healthy families, such as love, loyalty, steadfastness, and forgiveness, and those values made possible by such families, such as emotional resiliency, the capacity for enduring relationships, and generativity.
Thinking about the ethics of parenting in the framework of flourishing and mutuality is not meant as a way to find easy answers, but it is intended to protect against oversimplification—to ensure that what is morally most important about families remains at the center of our ethical reasoning and that no significant morally relevant consideration gets left out. Other ways of framing the ethical issues for parents may appear simpler at first glance, but in practice are at least as complex.
Take the case of Vicky and her parents. It should be easy for most parents to understand the parents’ desire to protect their daughter against nicotine addiction. They want to spare her from the diseases that accompany exposure to cigarette smoke. They might invoke a parent’s duty to protect their minor child from sources of harm, whether the actual harm occurs now or in the future. Vicky’s parents may be trying to balance the risks and benefits of using one of these interventions. It is never a trivial matter to decide which risks and benefits are relevant. If her parents focus exclusively on the risks and benefits to health, the decision may seem obvious: use whatever interventions are available to prevent nicotine addiction. Parenthood, unfortunately, is rarely that simple. By attending only to the direct risks to health, Vicky’s parents leave out many other important factors, such as the possibility that struggles with their daughter over control will impair the growth of mutual trust and respect and may lead to rebellion and backlash. Or Vicky may choose another, more rapidly destructive means of declaring her independence from parental control.
The point here is not that parents should absolve themselves from such decisions. They have an ethical obligation to make decisions about exactly this sort of issue. No, the point is that such decisions can be complicated ones, fraught with implications that go far beyond the near-term consequences for health. So, if as a framework the balance between risks and benefits is chosen, either all but a small subcategory of such risks and benefits must be set aside—those pertaining to health and safety—or the full range of relevant considerations must be acknowledged, deciding which ones are most important and weighing and balancing them. Vicky’s parents could approach this decision with a different moral framework—for example, the one suggested by such scholars as Dena Davis and Joel Feinberg. This framework gives priority to preserving
Vicky’s liberty to decide for herself, a liberty that would be constricted by addiction. The latter motive, preserving Vicky’s ability to choose, is captured in the ethical concept of the right to an open future. Davis (2001) offers a wonderfully clear summary of Feinberg’s (1980) classic distinction of four kinds of rights:
First, there are rights that adults and children have in common (the right not to be killed, for example). Second, there are rights that are generally held only by children (or by “child-like” adults). These “dependency-rights” … derive from the child’s dependence on others for such basics as food, shelter, and protection. Third, there are rights that can be exercised only by adults (or at least by children approaching adulthood), for example, the right to choose and to practice one’s religion. Finally, there are rights that Feinberg calls “rights-in-trust,” rights that are to be “saved for the child until he is an adult.” These rights can be violated by adults now, in ways that cut off the possibility that the child, when she or he achieves adulthood, can exercise them.
The concept of the child’s right to an open future gives wide discretion to parents’ judgments about how best to prepare their child for adult life. But it does not leave unlimited discretion. Parents who want to have their young child sterilized, perhaps because they believe that having children is a terrible burden they wish to spare their own child, would violate their child’s right to an open future by cutting off a life choice that is central to human flourishing—the decision whether to have and raise a child.
The right to an open-future framework gives a clear and resounding answer in a case such as sterilization. But, like other frameworks, the devil is in the details of the case. Feinberg and Davis disagree about a touchstone legal case that reached the U.S. Supreme Court in 1972. The dispute was over whether a state could insist that children remain in school beyond the eighth grade. An Amish community argued that requiring their children to stay in school could destroy their way of life and that their children were well prepared to function in Amish society. Feinberg concluded that the relatively minor infringement of a child’s right to an open future—perhaps 2 fewer years of schooling—was outweighed by the constitutional obligation not to unduly burden the Amish community’s religious beliefs. Davis (2001) strikes the balance on the opposite side. Once again, a variety of morally important considerations are at play, and once again, judgments are open to disagreement.
Other scholars defend a strong presumption in favor of parental authority over matters of health. Ross argues that “when there is parent-child disagreement, the child’s decision should not be decisive nor should health care providers … seek third party mediation. Rather … there are both moral and pragmatic reasons why the parents should have final decisionmaking authority” (Ross, 1997, p. 44).
A well-considered ethical decision will have to attend to the facts of the case. How effective is the vaccine? Is it safe? What is known about other young persons’ reactions to it? Do they substitute other risky behaviors for smoking, or does the vaccine reduce their overall risk? Further, a wise ethical decision will require reflecting on the implications
for Vicky’s developing moral character and for her relationship with her parents. Has Vicky been trustworthy? (Of course, as most parents of adolescents know, their children can be placed under enormous pressure to do unwise things and even very responsible teenagers can succumb, so “trustworthiness” remains a relative term.) Instead of a vaccine, might it be preferable to extract a promise not to use tobacco? If the promise is broken, privileges can be withdrawn. This option reinforces Vicky’s role as a moral agent rather than as someone who must always be protected against her own foolish choices. It also attempts to build mutual trust and respect between parents and child. Which decision is best depends on many factors—the medical facts, the child’s character and setting, the values at the heart of the family’s life.
An honest analysis will be no less complex in the second scenario: fifteen-year-old Larry and a vaccine against opiate addiction. Larry’s parents, most of all, want Larry to survive and not be drawn into the world of drug use, violence, and addiction. Their experience shows that this is a realistic danger for adolescents in their community. The medical risks of the immunotherapy must be taken into account, as well as the possible unintended consequences. For example, should Larry decide to try opiates despite having received the vaccine, he may have to use much larger doses to get high, which might pose even greater danger to his health. Responsible parents will want to know all they can about the medical risks and benefits, but also about the unintended but foreseeable medical, social, and legal consequences.
Individual physicians will need to be informed about all of these issues. If and when effective and apparently safe depot medications and immunotherapies are approved for marketing, some people will approach physicians to prescribe them for off-label use, even in the complete absence of data on their safety and effectiveness for such use, especially by children and adolescents. As soon as a clear picture of such requests emerges, professional associations should begin work on professional standards to guide physicians on how to respond.
Through law and regulation, public officials will be positioned to influence the patterns of use. If the potential for misuse were deemed high, the FDA could restrict access to some or all of these interventions. Other policy options could encourage their use by, for example, subsidizing them or requiring insurers to cover their cost.
In a climate in which substance abuse is seen as a scourge, many scenarios can be imagined. Might a state concerned about teenage drinking and driving make a depot medication against alcohol a condition for obtaining a driver’s license? Might a city rocked by the violence and chaos of a thriving market for cocaine or heroin embark on a mass vaccination program intended to dry up the market for these drugs? The rough
analogy here is with herd immunity in vaccinations against infectious diseases. Vaccinate a sufficient percentage of the population and the infection will not spread; vaccinate enough of the community against opiates and the dealers will move on to more lucrative markets.
Immunotherapies and depot medications for substance abuse are promising technologies with complex ethical implications. In thinking about these implications it is helpful to distinguish clearly between the issues that will arise in research and those stemming from their use. Likewise, in both research and use it is important to take into account the different modalities and the different purposes to which they might be put. This appendix discusses three modalities: active immunotherapies on the model of traditional vaccines but utilizing new methods for presenting small-molecule antigens to the immune system; passive immunotherapies such as mABs; and depot medications, including long-lasting forms of currently available drugs. The appendix also discusses three purposes of use: as therapy for overdose, for which mABs are the most promising of the three modalities; in relapse prevention protocols; and for protection protocols. All three modalities might be explored for both relapse prevention and protection purposes.
Responding to the challenges posed by immunotherapies and depot medications for substance abuse will require attention to the medical and scientific aspects of these interventions, as well as their social, economic, legal, and ethical implications. We must accept the great need to educate the public, health care professionals, and policy makers about the realities of substance abuse and its causes, prevention, and treatment. Failure to respond to the enormous educational challenge will contribute to misuse of these new interventions.
Once interventions that might be used in prevention protocols are approved by the FDA, clear and enforceable public policies will be needed to deal with off-label uses. These responses should include clear policies on the promotion of off-label use by manufacturers or others and clear guidance to the professionals, primarily physicians, who will have the power to control access to such interventions.
Finally, it should be anticipated that some, perhaps many, parents will seek to use certain interventions in the belief that they will protect their children against substance abuse, sparking a broad and heartfelt debate over the nature and limits of good parenting. This debate may well be the most far-reaching and long-lasting ethical consequence of immunotherapies and depot medications for substance abuse.
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