تصور غلط درمانی و تقدیر از خطرات در کارآزمایی های بالینی
|کد مقاله||سال انتشار||مقاله انگلیسی||ترجمه فارسی||تعداد کلمات|
|35275||2004||8 صفحه PDF||سفارش دهید||محاسبه نشده|
Publisher : Elsevier - Science Direct (الزویر - ساینس دایرکت)
Journal : Social Science & Medicine, Volume 58, Issue 9, May 2004, Pages 1689–1697
Studies repeatedly have shown that clinical research subjects have trouble appreciating the implications for their clinical care of participating in a clinical trial. When this failure is based on a lack of appreciation of the impact on individualized clinical care of elements of the research design, it has been called the “therapeutic misconception”. Failure to distinguish the consequences of research participation from receiving ordinary treatment may seriously undermine the informed consent of research subjects. This article reports results concerning appreciation of the risks of trial participation from intensive interviews with 155 subjects from 40 different clinical trials at two different medical centers in the USA. Working from transcripts of the interviews, every statement of a risk or disadvantage of trial participation was identified and coded into one of 5 different categories. Totally, 23.9% of subjects reported no risks or disadvantages in spite of being explicitly asked about them. Another 2.6% reported only incidental disadvantages such as having to drive a long way to get to the experimental site. In all 14.2% reported only disadvantages associated with the standard treatment (usually side effects). Another 45.8% told the interviewer about disadvantages and risks associated with the experimental intervention (usually side effects). Only 13.5% could report any risks or disadvantages resulting from the research design itself, such as randomization, placebos, double-blind designs and restrictive protocols. The results of this research suggest that subjects often sign consents to participate in clinical trials with only the most modest appreciation of the risks and disadvantages of participation.
It is now widely accepted that, except in a few specialized situations, a meaningful informed consent is a precondition for the ethical involvement of human subjects in clinical research. From the Nuremberg Code through the Declaration of Helsinki and the adoption of the so-called Common Rule for federally funded research in the United States to the most current debates on research ethics, there has been a growing consensus that subjects generally should not participate in clinical research without effective informed consent. What does informed consent require? US federal regulations, encapsulated in the so-called Common Rule (45 C.F.R. 46), require disclosure of at least eight elements: • The nature and purpose of the study, including that the study is research. • The reasonably foreseeable risks. • The foreseeable benefits. • Appropriate alternatives. • The confidentiality of the information collected. • An explanation of any compensation available for research with more than minimal risks. • Information about how the subject can get pertinent questions answered. • A statement that participation is voluntary. Disclosure of this information merely begins the process of obtaining informed consent. Ideally, subjects then combine the information with their own values and knowledge of their personal situation to make decisions that fit their needs and values. Although it is probably legally not necessary for subjects to understand the information disclosed, if informed consent is to achieve its goals of promoting autonomous and rational decision making (Berg, Appelbaum, Lidz, & Parker, 2001; Faden and Beauchamp, 1986), it is important that subjects not only understand the elements of the disclosure, but also appreciate its applicability to their own situation. Subjects who lack the capacity to undertake any one of these tasks may be incompetent to make a decision about participation. But even subjects with the capacity for these functions may not be able to make decisions in this manner for many reasons (e.g., because the disclosure was inadequate or because of a lapse in attention to the disclosure). In this paper, we concentrate exclusively on subjects’ appreciation of the risks of participating in clinical trials. Whereas understanding requires an ability to grasp the meaning of the information disclosed, appreciation involves the recognition of the relevance of that information for one's own situation ( Appelbaum & Grisso, 1988). Thus, subjects can understand that half of the participants will receive placebo without appreciating that they too run a 50% risk of not getting active medication ( Appelbaum, Roth, & Lidz, 1982). Appreciating how risks may affect one's own situation is obviously only one component of a full appreciation of the consequences of participating in a clinical trial, but it is certainly a critical component. It is difficult to imagine a person making an autonomous, rational decision about participation in a trial without an appreciation of both the risks and the benefits of participation. The difference between the risks of treatment and of research There are major differences between the basic ethical requirements of doing research and providing treatment. In the treatment setting, the clinician owes a primary allegiance to the patient's well-being. Fried calls this allegiance the principle of “personal care” (Fried, 1974). Researchers—even when they are also clinicians and their studies involve the provision of treatment—have a different and competing obligation. They must insure that their studies generate valid data (Shatz, 1990). This obligation derives from the commitment that researchers make to the scientific community, which depends on the validity of their results; to funding agencies, which support research that will yield generalizable findings; and to research subjects themselves, who are promised that their participation will lead to socially useful knowledge. To be sure, clinical researchers are ethically obligated to guard their subjects from needless harm (Nuremberg Code, 1946). But many of their decisions inevitably are not aimed at maximizing the benefits that specific subjects receive (Churchill, 1980; Hellman & Hellman, 1991). The competition between the need to collect valid data and protecting the best interests of the patient/subject is manifest in many ordinary techniques of clinical research: • Subjects typically are assigned to treatment conditions randomly, rather than on the basis of an individualized judgment as to which treatment will best meet their personal needs. Although the treatments being randomized may be in collective equipoise (i.e., there may be no evidence that any one treatment is better than another), this may not be true for the individual. For example, Appelbaum et al. (1982) reported that some subjects in their study had previously failed to improve on one of the medications to which they were randomized. • Subjects may receive placebos for reasons unrelated to improving their condition, something that would not occur in ordinary clinical settings. Although often placebo controls are not used when there is evidence for the effectiveness of one of the treatments being tested, placebo controls are frequently used in studies of depression and other disorders, even when there exist medications that are widely thought to be effective (Carpenter, Appelbaum, & Levine, 2003; Charney, 2000; Miller, 2000). • Clinicians may be expected to treat subjects without knowing which of the several treatments being provided in the study the subject is receiving and, similarly, subjects may be kept ignorant of which treatment they are getting (a “double-blind” procedure). Although studies in which treating clinicians are blind to the treatment being used typically have protocols available for, e.g., managing side effects, clinicians’ and subjects’ abilities to recognize physical and mental symptoms as related to the intervention they are experiencing may be impaired by their ignorance about the identity of the treatment involved. In an emergency, the blind can be broken, but researchers are often hesitant to do that because it involves losing a subject from the study and risks biasing the sample. • A protocol, rather than patients’ responses to treatment, will often determine the dosage of medication that an individual subject receives, responses to side effects, and the like. In circumstances in which physicians might increase the amount of medication prescribed in response to a patient's failure to improve on the current dose, many study protocols restrict the ability to search for the optimal dose for each patient/subject. In addition, although a systematic response to side effects as embodied in many protocols may be advantageous, different patients not only respond differently to different interventions but also to different ways of minimizing side effects. • Other adjunctive medications or treatments may be prohibited to the subject, not because they are harmful in conjunction with one of the experimental treatments but precisely because they may be helpful and thus create confusion about the source of any positive responses observed. These compromises with patients’ best interests are not made lightly (see, e.g., Gifford, 1986; Freedman, 1987; Schafer, 1982, Kopelman, 1983; Makuch & Johnson, 1989; Volavka, Cooper, Laska, & Meisner, 1996; Zelen, 1979). Nonetheless, from the point of view of the subject, the degree of compromise of personal care may involve relevant risks. The limitations on personal care built into the design of a clinical trial are an important risk that needs to be appreciated for any subject giving a valid informed consent to participate. The failure to appreciate that elements of research design may limit the degree of individualized care has been called the “therapeutic misconception” ( Appelbaum et al., 1982; Appelbaum, Roth, Lidz, Benson, & Winslade, 1987). None of this should be taken to suggest that it is not reasonable for an individual to join a clinical trial. Clinical trials are often staffed by the exceptionally well-trained individuals, who may have more time and resources to provide to their subjects than would be available in ordinary clinical settings. Newer and more effective treatments may be available only in the context of a clinical trial. Our point is not that it is never a reasonable choice to join a clinical trial but that some features of trials involve disadvantages that subjects should appreciate if they are going to weigh them against the benefits that may also be available. The concept of the therapeutic misconception The therapeutic misconception has been described as occurring when a research subject, failing to grasp the distinction between the imperatives of clinical research and of ordinary treatment, inaccurately attributes a primacy of therapeutic intent and individualized care typically seen in ordinary clinical settings to research procedures. Most often, this will occur in clinical research, but it can also occur in non-clinical settings. Growing concern about the validity of consent obtained from many research subjects has caused some commentators and expert panels, e.g. the National Bioethics Advisory Commission (NBAC) (1998), to suggest that the therapeutic misconception may constitute a major obstacle to meaningful decision making. The existence of a therapeutic misconception is not equivalent to mere failure on the part of a subject to understand the elements of informed consent to a research study. Of course subjects may fail to understand the research and also have a therapeutic misconception, but subjects may also fail to understand the nature of a study or the procedures that they will undergo, yet avoid attributing therapeutic intent to the research. The converse of this is also true. Understanding the goals and methods of a research project (e.g., double-blind procedures) does not mean that subjects will avoid assuming therapeutic motivations for them. Subjects may believe that such procedures have therapeutic objectives (e.g., “If I know what I’m getting, I’ll talk myself into believing that it won’t work.”) or that investigators can decide which treatment works best in general by determining which one works best for each subject in the study. Nor are all failures of appreciation necessarily associated with therapeutic misconceptions. For example, subjects may not appreciate how their subsequent decision to withdraw from a research study will impact them (“I’ll have to go somewhere else to be treated”.) without misconstruing the difference between being in a study and receiving ordinary clinical care. The core of the therapeutic misconception is subjects’ failure to grasp that the risks they face from participating in research protocols are inherently different from those involved in receiving ordinary treatment. Put differently, subjects manifest a therapeutic misconception when they fail to appreciate the risks and disadvantages to participating that are inherent in the research design. This paper focuses on subjects’ appreciation of risks and disadvantages related to the design of clinical trials. Empirical research on the therapeutic misconception Since the initial description of TM by Appelbaum et al. (1982), a number of studies have found indications that its occurrence is not uncommon in clinical research. Subjects appear frequently to overestimate the likely benefits of entry into research studies (Penman et al., 1984, Schaeffer et al., 1996), to underestimate risks (Joffe, Cook, Cleary, Clark, & Weeks, 2001), to be confused about the nature of randomized assignment (Featherstone & Donovan, 2002), and generally to conflate research with ordinary treatment (Joffe et al., 2001). The Advisory Committee on Human Radiation Experiments (ACHRE) summed up its findings regarding the common failure to appreciate the risk/benefit ratios of research participation based on interviews with 1882 patients drawn from cardiology and oncology clinics, of whom 505 had been research subjects, in this way: “Patient-subjects frequently expressed the belief that an intervention [i.e., research participation] would not even be offered if it did not carry some promise of benefit; many certainly assumed that the intervention would not be offered if it posed significant risks” (ACHRE, 1995). We undertook this research in order to determine the frequency of the therapeutic misconception, describe it correlates and ascertain its relationship to other aspects of understanding. This required us to develop a procedure for measuring therapeutic misconception because there has been no systematic way of measuring it. In a recent paper (Appelbaum, Lidz, & Grisso, under review), we described a procedure that involves coding semi-structured interviews for two features: (1) the belief that the treatment would be individualized to the subject and (2) an unreasonable assessment of benefit, based on a failure to grasp the consequences of the methodology of the study (i.e., subject endorses a type or degree of benefit precluded by the design of the study). Using this system, we concluded that 62% of our sample had evidence of a therapeutic misconception on one or both of these dimensions. Although this sounds like a high rate, it might be a conservative estimate because therapeutic misconception was not coded unless there was an affirmative statement that met one or the other of the above criteria.