Statement of Commissioner Bernard Lo, M.D.

Research on persons with impaired decisionmaking capacity raises ethical dilemmas. It is ethically troubling to enroll such persons in research that offers no direct clinical benefit, because they may be exploited or encounter risks that they did not accept. These ethical concerns are greater as the level of risk increases. On the other hand, research that provides no direct benefit to subjects may advance our understanding of the pathophysiology of brain disorders and lead to therapeutic advances. Often such research cannot be done on patients who do not have active disease that impairs their decisionmaking capacity. Sound public policies need to protect vulnerable research participants from harm, but should also recognize that the development of effective therapies depends on research that provides no direct benefits to participants. Since I began medical training some 25 years ago, treatments for depression, schizophrenia, bipolar disorder, and Parkinson’s disease have dramatically improved. These therapeutic advances depended upon research that involved more than minimal risk and offered no direct benefit to participants who had impaired decisionmaking capacity.

The Commission heard about research projects in which persons with impaired decisionmaking capacity due to mental disorders were not adequately protected. These incidents involved drug withdrawal studies, provocation studies, and research involving institutionalized persons. The Commission wisely recommends tighter restrictions on these kinds of research, which offer no prospect of direct benefit and involve risk that is far greater than minimal risk. In providing better protection in these situations, however, the Commission’s recommendations also raise barriers to research that involves only small increases over minimal risks and is likely to result in important knowledge about the participant’s disease. Hence, the recommendations will thwart a better understanding of the pathophysiology of the diseases that impair decisionmaking capacity, while providing little additional protection to vulnerable subjects. This is not the correct balance between protecting vulnerable persons and developing better treatments for patients with brain disorders. We should focus new protections where they are most needed. In an effort to correct some problems, we have created new ones.

Some examples will illustrate why such research should be permitted. In patients with mental illness and impaired decisionmaking capacity, PET scans or other imaging studies may illuminate pathophysiology in ways that may lead to better therapies, better methods to evaluate potential therapies, or better ways to identify persons who are likely to respond to treatments. These imaging studies may be greater than minimal risk in patients with dementia or schizophrenia, who may be particularly agitated by such procedures. Yet the increase over minimal risk is small. Discomfort is transient and will not lead to worsening or relapse of the underlying disease. These are not the kinds of studies that have raised alarm among patient advocates or bioethicists. They need not be the target of additional regulations.

Protocols can be required to take precautions to reduce the risk of imaging studies. First, some measures are standard clinical practice. Patients undergoing imaging studies often are offered music to reduce anxiety and agitation, or mild sedatives if needed. In addition, the radiologist directing the imaging study, who is independent of the research team, is readily available to assess the patient’s reaction to the intervention and to terminate the procedure if needed. Second, the research protocol can take additional protections. Persons who have gotten anxious or agitated at previous imaging studies, or have refused such studies in the past, should be excluded. IRBs may require further protections if subjects are institutionalized or when the principal investigator is also the patient’s clinician. Third, protections applicable to all research on persons with impaired decisionmaking capacity apply here. The Commission’s recommendations clarify and extend such protections. Objection by the subject at the time of enrollment or at the time of the imaging procedure will be heeded. Thus, if a subject objects or becomes agitated, the procedure will be terminated. I believe that with such protections the risks of neuroimaging studies should be permitted if a study offers the prospect of important understanding of the underlying mental disorder.

After debating these issues, the Commission recommended a new federal panel to identify categories of acceptable research that were greater than minimal risk and offered no prospect of direct benefit to participants who lacked decision-making capacity. Local IRBs would be permitted to approve protocols that fall within those categories. I welcome the idea of identifying such types of research and providing guidance to IRBs. However, we do not need another committee to decide that research projects using PET scans may be permitted. Convening a national panel will involve substantial delay. I would prefer that the Commission follow the federal regulations for research on children and permit research that involves small increases over minimal risk and offers the prospect of substantially enhancing our understanding of the condition that impairs the subject’s decisionmaking capacity.

Commissioner Laurie M. Flynn concurs with Dr. Lo’s statement.

Statement of Commissioner Alexander M. Capron, LL.B.

I agree in large measure with the Commission’s recommendations but arrive there by a somewhat different path and by giving different weight to the evidence we considered. I set forth my reasoning separately for two reasons. First, I think the report gives IRB both too little and too much authority. As to the latter, I believe it is too soon to know whether the SSP ought to issue "guidelines" under which local IRBs could approve otherwise unapprovable protocols (those involving more than minimal risk and no prospective benefit to subjects, to which the prospective subjects have not given consent or prospective authorization) without the more visible and disinterested review of the SSP itself (see Recommendations 2B and 12C). I believe this possible route for approval should be considered only after more is known about the panel’s workload and work products and after general improvements have been brought about in the process for local review of protocols. At the same time, I believe Recommendation 6 is wrong in restricting the role of "third parties," which could preclude consent auditors appointed by an IRB under existing regulations from monitoring the process to protect potential subjects.

The second and more important reason for writing separately is because I am afraid that some readers, when evaluating the merits of the criticism this report is likely to face from the research community, will not find in this report the full set of considerations that led the Commission to its conclusions. At the heart of our deliberations has been the tension between a more traditional focus on protecting human subjects against undue harm from biomedical research and the current focus on protecting them from being excluded from research. While circumstances certainly arise in which the latter view has much to recommend it, I believe that its ready acceptance over the past decade is largely a result of a collective "therapeutic misconception," that is, construing research interventions as beneficial to subjects (especially those for whom no other effective medical interventions are available) even when the prospect of benefit is nonexistent or at best extremely remote.

It would be understandable if patients suffering from any disease for which no cure exists (along with the families and physicians of such patients) were skeptical of the caution expressed 30 years ago by philosopher Hans Jonas that scientific progress is an optional goal that ought not be sought at the expense of other more fundamental social values. And—as the testimony to the Commission of professionals and lay persons alike has made clear—there may be no field of medicine today in which the sense of frustration over the absence of cures is greater, or the desperation of patients and their families and physicians more intense, than in the treatment of mental illnesses, particularly those conditions that radically compromise their victims’ ability to function successfully in the world, to "be themselves," and to live their lives with a justified sense of safety and security that most Americans take for granted. Yet it is precisely in these circumstances—when research would involve patients many of whom are made very vulnerable both by their illness and by the nature of the care they receive, and some of whom reside at the margins of society, frequently invisible, largely powerless, and often friendless—that Jonas’ caution has most to recommend it.

The cautions and limits recommended in this report, and other more far-reaching protections that the Commission discussed but did not adopt, have drawn heated protests from those who view as a greater wrong the opportunities for progress in understanding, ameliorating, and even curing mental disorders they believe will be lost if special regulations are adopted. It is no answer to their objections that much of the research in question—including some that would expose subjects to more (perhaps substantially more) than minimal risk—will in the end not significantly advance medicine’s knowledge or skills, and indeed, that a large portion of the studies (especially those that are commercially sponsored) aim at nothing more than achieving regulatory approval for drugs that differ only in minor ways from treatments that are already available. Whatever the accuracy of such replies, those, such as the Commission, who favor placing some restrictions on research in the name of protecting subjects must recognize that we thereby deprive the populations of which those subjects are a part of any additional benefits unfettered research would provide beyond the benefits that can be achieved when more protective rules are followed. That dilemma is age-old, and at least for the last half-century, the civilized world has stood on the side of forgoing such additional benefits as are lost from adhering to ethical standards aimed at protecting subjects’ rights and welfare.

Why, then, are the Commission’s efforts to ensure appropriate protections for patients with mental disorders so roundly resisted and met with claims that the recommendations will doom progress in the field by rendering critically important studies impossible? It is very simply that the paradigm that permits other sorts of research to go forward—in which subjects personally provide voluntary, informed consent to participate in research that an IRB has previously deemed acceptable on risk-benefit and justice grounds—is inapplicable to studies that would utilize subjects whose mental disorders render them incapable of agreeing to participate in an informed and voluntary fashion.

Although the Commission repeatedly emphasizes that mental disorders do not necessarily render people unable to give valid consent, some critics suggest that our conclusion that researchers need to arrange an "appropriate" assessment of potential subjects’ decisionmaking capacity unfairly stigmatizes subjects. Telling a potential subject that the research design requires that his or her capacity be evaluated will not stigmatize the subject in the world’s eyes but will remain a matter entirely within the confidential relationship between the potential subject and those involved in some fashion in carrying out the research project, including any monitors assigned by the IRB. As any competent patient would quickly realize, such a requirement reflects no disrespect for potential subjects, though it may indicate some concern about the conflicting motives of researchers.

Nor would the norms of fairness be violated by imposing such a requirement here when none exists for research generally. Even if the common sense ground that such a requirement makes particular sense when research involves conditions affecting the organ of consent were not true (that is, even if an empirical investigation were to reveal that decisionmaking capacity is just as likely to be as compromised among patients suffering from other conditions), it hardly seems prejudicial to insist that reasonable steps be taken to ascertain that subjects can actually provide voluntary, informed consent. The objection of unequal treatment would seem much more fitting coming from researchers on mental disorders if they already routinely used appropriate means to assess their subjects’ decisionmaking capacity and were simply urging that investigators in other areas of research with human beings ought also to be held to this same standard. Yet in the Commission’s review of the protocols that underlay a number of recently published studies in this field—which were solicited because they all involved more than minimal research and many of which involved patients with very serious psychiatric conditions—not a single one evinced any effort by the researcher to assess subjects’ decisional capacity, nor was any such requirement apparently imposed by any IRB in approving these protocols. The failures (if any) of researchers in other fields does not excuse this lack of interest among psychiatric researchers regarding one of the basic prerequisites of ethical research. Insisting that capacity be appropriately assessed does not contradict the presumption, which applies to these patients as to every other, that all adults are competent, whereas ignoring the prima facie need for an evaluation makes a mockery of that presumption by rendering it nothing more than a convenient rationale for ignoring the invalidity of the "consent" obtained from some subjects. History may show that, like every swing of the pendulum, the present Commission’s recommendations went further to protect subjects than was necessary and were more restrictive of investigators’ freedom than was required. One thing is certain: with the failure of the federal government to include in its human subjects regulatory scheme any version of the special protections recommended 20 years ago by the National Commission for the Protection of Human Subjects, abuses have occurred that could—and should, and probably would—have been prevented had some version of that commission’s recommendations been adopted. On balance, the rules and official actions recommended by the Commission are the minimum needed. They should be acted upon without further delay.

Commissioner Patricia Backlar concurs with Professor Capron’s statement.

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