Mentally Disabled and Mentally Ill Persons: II. Research Issues

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II. RESEARCH ISSUES

Protecting the interests of mentally ill and disabled people entails a delicate balance between two aims: a rigorous program of research into their medical problems and attention to the difficulties involved in using those people as subjects of research in ethically appropriate ways. Although the hope of understanding mental illnesses and disabilities depends on the results of medical research, persons who have those conditions are especially vulnerable to exploitation and abuse.

Research Guidelines

There are two major problems in conducting research on mentally ill and disabled persons. The first is competence, or decision-making capacity: Because of the nature of their problems some mentally ill and disabled subjects may not be able to make informed decisions about whether to participate in a research protocol. Issues surrounding informed consent are made even more problematic by the fact that mentally ill or disabled subjects may be living in institutions for patients with special mental disorders, and institutionalization can exert pressures that compromise a person's ability to make a free choice about participating in research. The second problem involves risk and the design of research studies. Under what circumstances, if any, can a mentally ill or disabled person be exposed to the risk of harm in a research study?

Some mentally ill or disabled persons may be incapable of giving valid informed consent to participate in a research study. However, prohibiting those potential subjects from participating would rule out much medical research that could benefit the subjects and others with similar disorders, in the long run harming the populations the studies are intended to protect. For that reason, since the last two decades of the twentieth century there has been a consensus that research on mentally ill and disabled persons can be justified in some cases, subject to certain conditions (National Bioethics Advisory Commission [NBAC]; Royal College of Psychiatrists [RCP]; Royal College of Physicians of London [RCPL], 1990; U.S. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1978, 1979; Wing; World Medical Association; National Institutes of Health; Medical Research Council of Canada [MRCC]).

Perhaps the most important of those conditions is the stipulation that research on incompetent mentally ill or disabled persons should be allowed only if that research cannot be done on competent persons (National Bioethics Advisory Commission; Wing; U.S. National Commission for the Protection of Human Subjects, 1979). The guidelines for biomedical research proposed by the World Health Organization (WHO) and the Council for International Organizations of Medical Sciences (CIOMS) make that requirement explicit, arguing that because of the risks and burdens involved, medical research should not be done on individuals who are unable to choose to participate if it can equally well be done on competent adult volunteers (World Health Organization).

A second condition concerns the amount of risk to research subjects that may be allowed. Many professional and regulatory bodies state that research on incompetent subjects such as children and the mentally ill or disabled ordinarily is approvable only when the research involves a minimal risk or a minor increment over minimal risk to the subject ("Federal Policy for the Protection of Human Subjects"; Royal College of Physicians of London, 1996). According to this reasoning, some research on mentally ill or disabled persons may be ethically justifiable, subject to specific additional conditions, even if it is nontherapeutic (Wing; National Institutes of Health).

Of course, there is considerable room for controversy in defining minimal risk. U.S. federal policy compares minimal risk to the risks of the everyday life of a potential subject or those of a routine physical or psychological examination ("Federal Policy for the Protection of Human Subjects"). The Royal College of Physicians of London (1996) defines minimal risk as covering two types of situations: those that might involve negligible psychological distress, including other trivial reactions such as a mild headache or a feeling of lethargy, and those that involve very remote risks of serious injury or death, comparable with the risk of flying in a scheduled passenger aircraft.

It is widely agreed that research proposals involving mentally ill or disabled persons should be approved by an ethics committee charged with reviewing research proposals, such as an institutional review board. Research should not proceed if a competent subject objects. When a subject is unable to give properly informed consent, consent should be sought from an appropriate surrogate decision maker, such as a relative (World Medical Association).

Competence and Informed Consent

A fundamental ethical requirement for most medical research is the informed consent of the subject. For consent to be valid the subject must be capable of understanding the relevant implications of his or her decision to participate: the purpose, nature, and duration of the research; its possible risks and benefits; and so on. Because of the nature of some mental disorders, it is often unclear whether a mentally ill or handicapped person is capable of giving proper informed consent. Although many mental illnesses and disabilities do not affect those capabilities, it is the duty of a medical researcher to ensure that a potential subject of research is capable of making an informed decision whether to participate.

The ability to make that decision often is termed competence or decision-making capacity. A competent person should be capable of making a decision for which he or she legitimately can be considered accountable (Elliott). Competence ordinarily is defined in relation to a particular activity; a person can be competent to make some types of decisions but not others. For that reason assessments of competence ordinarily should focus on the task at hand, in this case understanding the implications of participating in a particular research protocol.

Most proposed standards for assessing competence focus on the process of reasoning involved in making a decision rather than on the outcome of the decision (U.S. President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, 1982; Buchanan and Brock; National Bioethics Advisory Commission). Because each person has different needs and values, often there is no single decision that can be judged correct for everyone. However, focusing primarily on a person's reasoning processes also can be problematic. A competent person sometimes may use faulty reasoning or make irrational decisions yet still be considered accountable for his or her choices (Elliott).

Probably the most influential tests of competence have dealt with consent to treatment rather than to research. A U.S. President's Commission report (1982) relates competence to three aspects of a person's mental abilities: (1) the possession of a set of values and goals, (2) the ability to communicate and understand information, and (3) the ability to reason and deliberate about one's choices.

However, competence criteria that focus primarily on rationality and reasonable deliberation may not be very helpful when the person making the choice has an affective disorder. For example, patients with depressive delusions may consent to hazardous research because they think they deserve to be punished (Elliott; Kopelman).

Furthermore, a mentally ill or disabled person may be able to satisfy a criterion partially but not fully or may be able to satisfy only some criteria. In cases like these it is a matter for debate how high the standards for competence should be set. For this reason some writers and professional bodies, including the U.S. President's Commission (1982), have endorsed a sliding-scale approach to assessing competence (National Bioethics Advisory Commission).

With this approach standards of competence are set higher for interventions with a risk-benefit ratio that is relatively worse and lower for interventions with a riskbenefit ratio that is relatively better. For example, to participate in a research protocol whose risks are great and whose benefits are small a subject might have to show not only that he or she understands the facts and issues but also that he or she appreciates the nature of the situation. This may be a very high standard of understanding: an affective as well as a cognitive recognition of the nature of the research, an awareness of how others view the decision, and an understanding that he or she has a mental disorder that is appropriate for study. In contrast, if the risk-benefit ratio is much better, the standard for competence might be set very low, for example, merely showing evidence of a choice to participate.

Even when a subject is clearly incompetent to give informed consent, many writers believe that research should not be done without the subject's assent; that is, researchers should ensure that the subject, to the degree that he or she is mentally capable, agrees to or expresses a positive interest in participating in the research. Research is much more difficult to justify when it is done in spite of a subject's verbal or behavioral objections (Wing). However, it is arguable that research without a patient's assent is justifiable if the patient is clearly incompetent and the research is therapeutic, involves minimal risk, has been consented to by an appropriate surrogate, and is clearly in the best interests of the patient.

Issues of competence and informed consent can be especially problematic in certain mentally ill patients whose competence may change over time. In the case of therapeutic research, for example, on antipsychotic medication, a research protocol may restore to competence a patient who previously was incompetent. In these situations the possible value of restoring the patient to competence should be part of the decision whether to enroll the patient in a research protocol. In cases in which a patient's competence fluctuates over time researchers should try to obtain consent at a time when the patient is best able to give it.

Further provisions may be needed to protect the interests of mentally ill and disabled patients who are incompetent or whose competence is questionable. The Belmont Report recommended that researchers seek the permission of third parties who are most likely to understand a subject's situation and act in that person's best interest (U.S. National Commission for the Protection of Human Subjects, 1979; National Bioethics Advisory Commission). Two standards have been employed widely in making decisions for incompetent patients: the best interests standard, in which third parties make decisions that are based on the interests of patients through the use of socially shared values, and in the case of previously competent patients the substituted judgment standard, by which third parties make decisions that are based on values and preferences the patient may have expressed in the past. The Belmont Report made the additional recommendation that those third parties be allowed to observe the research as it proceeds, with the option of withdrawing the subject from the research at any time (U.S. National Commission for the Protection of Human Subjects, 1979; National Bioethics Advisory Commission).

Institutionalized patients are often especially attractive as research subjects because their medication, diet, and compliance with a study can be monitored and controlled easily. Nevertheless, many writers have argued that institutionalized populations deserve special protection, pointing out the examples of the Willowbrook State School in New York, where mentally retarded children were injected with the hepatitis virus in 1956, and the Jewish Chronic Disease Hospital in Brooklyn, where nineteen chronically ill patients were injected with cancer cells in 1962 (U.S. National Commission for the Protection of Human Subjects, 1978; Kopelman). Some observers have argued that the fact of institutionalization invalidates informed consent and that research on mentally ill or handicapped persons in institutions should be ruled out entirely.

There are several grounds for the argument that institutionalization invalidates informed consent. One that has been rejected widely is that any person who has a mental illness or disability severe enough to warrant institutionalization is mentally incompetent to give informed consent. However, many people have illnesses or disabilities that impair them in ways that require institutional treatment but do not impair their ability to make competent judgments about participating in research. A second argument is that institutionalization itself deprives people of the ability to make their own decisions, for example, by placing them in a situation of constant subordination to authority (Annas et al.). A third argument is that institutions severely limit the choices available to their patients, thus placing constraints on their freedom of choice. Research on institutionalized patients also can be difficult for impartial external observers or regulatory bodies to monitor effectively. For these reasons many agencies and professional bodies require that researchers take special measures to guard against the manipulation of institutionalized subjects.

Risk and Study Design

At the turn of the twenty-first century a number of studies of mental illness attracted considerable criticism because their designs exposed subjects to an unacceptably high ratio of risk to benefit. The most controversial of those studies were placebo-controlled trials, symptom-provocation studies, and relapse studies.

PLACEBO-CONTROLLED TRIALS. The ethical controversy over certain placebo-controlled trials begins from the principle of clinical equipoise, according to which, before a randomized clinical trial can be started there must be genuine disagreement in the community of expert practitioners about which treatment is preferable (Freedman, 1987). If there is disagreement about whether a new psychiatric drug is superior to placebo, clinical equipoise would permit a trial to settle the question. However, would it be ethical to begin a trial comparing a new drug to placebo if there already was an effective standard treatment for the illness in question? According to the requirement for clinical equipoise, the answer is no.

Clinical equipoise is rooted in standards of sound clinical practice. The treatments offered to patients in a clinical trial must be in equipoise with the prevailing standard of care for the subject population in question so that the clinical care of those patients will not suffer as a result of enrollment in the trial. The Declaration of Helsinki states, "The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods" (World Medical Association).

In light of the proven efficacy of many psychiatric agents, it might be expected that placebo-controlled trials in psychiatry would be rare. However, new psychiatric agents are tested routinely against placebo even when failure to treat the illness in question adequately could cause serious harm to the subjects enrolled in the trial, such as patients with schizophrenia or major depression. Indeed, representatives of regulatory agencies such as the U.S. Food and Drug Administration and the Canadian Health Protection Branch have encouraged the use of placebo-controlled trials, especially in psychiatry, arguing that those trials are the only way to determine whether a new drug is effective (Addington). Defenders of placebo-controlled trials also argue that subjects are protected by the requirement for informed consent and that even if a subject's mental illness worsens during a trial, the symptoms of such illnesses are temporary, reversible, and not sufficiently harmful to warrant a prohibition against placebos.

It is difficult to see how major depression and psychosis can be considered insufficiently harmful to subjects, especially when both conditions are associated with a higher risk of suicide. It is also doubtful that informed consent will protect research subjects from enrolling in potentially harmful studies. Many investigators do not conduct an adequate discussion with patients about the risks and disadvantages of taking part in a study, and even when investigators disclose those risks, many patients do not understand them fully (Appelbaum et al.).

The requirement for clinical equipoise does not mean that all or even most placebo controls are unethical. As Benjamin Freedman (1990) has noted, placebo controls are justified in testing treatments for conditions:

that have no standard therapy,
whose standard therapy has been shown to be no better than placebo,
whose standard therapy is placebo,
whose standard therapy has been called into question by new evidence warranting doubt about its net therapeutic advantage, and
whose validated optimal treatment is not made freely available to patients.

Charles Weijer points out two additional situations in which placebo controls are permissible. If a particular population has failed to respond to first-line treatments for a condition and no proven second-line treatment exists, that population may be enrolled in a placebo-controlled trial. Also, if a new treatment simply is added onto a standard treatment, that treatment may be tested against placebo as long as all the subjects in the trial get the standard treatment either with the add-on or with placebo.

SYMPTOM-PROVOCATION STUDIES. Another controversial psychiatric study is the symptom-provocation study or challenge study. The purpose of those studies is to learn more about the pathophysiology of mental illnesses by provoking their symptoms in mentally ill subjects. For example, in a number of different studies published in the 1990s researchers gave schizophrenic subjects a variety of psychoactive drugs to exacerbate the symptoms of psychosis. Symptom-provocation studies have generated far more outrage in the popular press and among patient advocacy groups than in the bioethics and medical literature, in which they have been defended for their scientific merit (Whitaker; Miller and Rosenstein). However, in those studies, unlike most clinical trials, mentally ill subjects often are exposed to risks without any expectation of therapeutic benefit. Also, unlike many Phase I clinical trials, symptom-provocation studies are performed not on healthy volunteers but on ill patients. Indeed, the very purpose of those studies is to induce harmful symptoms in patients who already have mental disorders.

RELAPSE STUDIES. A third source of controversy in psychiatry involves relapse studies or washout studies. In relapse studies mentally ill subjects are taken off their regular medications to determine whether they will relapse into their illnesses, how long it will take them to relapse, or whether their health can be maintained without medication. In a widely reported study at the University of California at Los Angeles that began in the 1980s, researchers required that subjects with schizophrenia who had recovered from their symptoms be taken off their medication. After the study was concluded, a subject committed suicide (Katz; National Bioethics Advisory Commission).

Defenders of relapse studies have argued that many mentally ill patients, particularly those with schizophrenia, are maintained on medications that can cause serious and irreversible side effects and that "drug holidays" are often an accepted part of standard therapy. Critics point out that it is in the interests of most patients to be maintained on the therapeutic regimen that has worked for them, that such patients are not informed of the risks of relapse studies, and that a relapse may increase the risk of future relapses (Katz; Shamoo and Keay).

carl elliott (1995)

revised by carl elliott

susan parry

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