Phase I oncology trials: why the therapeutic misconception will not go away

Short abstract

In many cases, the “therapeutic misconception” may be an unavoidable part of the imperfect process of recruitment and consent in medical research

Paul Appelbaum, Loren Roth, and Charles Lidz coined the term “therapeutic misconception” in 1982.¹ They described it as the misconception that participating in research is the same as receiving individualised treatment from a physician. It referred to the research subject's failure to appreciate that the aim of research is to obtain scientific knowledge, and that any benefit to the subject is a by‐product of that knowledge. More recent studies by Appelbaum and Lidz have shown that this phenomenon is just as pervasive now as it was twenty four years ago.² The problem pertains not to any duty of care for researchers but to participants' unfounded belief in the therapeutic potential of research.³ It is especially acute in phase I oncology trials, which aim to test the toxicity and highest tolerable dose of anticancer drugs.

To remedy this situation, many have argued that both clinicians and researchers need to do more in explaining to subjects the differences between experimental research and standard care. Clinicians and researchers recruiting potential subjects for research must present information about the expected risks and benefits of participation in research in a more realistic and straightforward way.⁴ In one recent examination of consent forms for phase I oncology trials, Sam Horng et al found that, in the section on “benefit”, only one of 272 forms stated that the subjects were expected to benefit. They also found that 11 consent forms (four per cent) stated clearly that subjects would not benefit, 25 forms (nine per cent) communicated uncertainty about benefit, and 5 forms (two per cent) said nothing about the chance of benefit. Interestingly, 139 forms (51 per cent) alluded to the possibility of benefit in a section other than the designated “benefit” section.⁵ In the light of this, it is imperative that all phase I consent forms prominently state that the research is not expected to benefit the participant. More specifically, they should state that there is an overall complete response rate of 0.5 per cent and a partial response rate of 1.5 per cent (total response rate two per cent) in phase I oncology trials.

Nancy King has proposed that we distinguish three types of research benefit: direct benefit, collateral benefit, and aspirational benefit.⁶ Direct benefit is defined as benefit that results from the subject receiving the intervention being studied, or its therapeutic physiological benefit. Collateral (or indirect) benefit results from being a subject in a trial, even if one does not receive the experimental intervention. Collateral benefit can be physiological or psychological and includes what is known as “inclusion benefit”, the benefit gained from participation itself. Aspirational benefit is the benefit to society and future patients, which follows from the results of the study. King points out that research subjects often confuse these different senses of “benefit”.

In many cases, it is the desire or hope for direct benefit, a positive physiological response, which motivates people to participate in medical research. Even if clinicians and researchers carefully explained the differences between clinical care and research to patients, and even if consent forms prominently stated that subjects were not likely to benefit from participating in research, it would reduce the incidence of, but not eliminate, the therapeutic misconception. Indeed, it would be naïve to think that it could be prevented in every case. This misconception is one manifestation of a deep seated phenomenon of human psychology: the unique combination of emotion and reason in individual decision making.

How an investigator or clinician explains information about research must not be equated with how a subject processes and interprets that information. What the information means to the subject is not solely a function of how it is presented. In addition, it depends on beliefs and emotions such as fear and hope. These emotions can and often do influence how a subject interprets medical information, particularly with respect to the weighing of risks and benefits of participating in research, as well as what the subject expects from participating. Depending on how they present and explain this information, researchers can influence a potential subject's reasoning. They cannot, however, determine how the subject's emotions ultimately figure in the decision whether or not to participate in a clinical trial. There are both objective and subjective components to how one interprets medical research. The subjective component can play a significant role in a person's deliberation and decision about whether or not to enter a trial.

There is more to rationality and decision making about whether to take part in medical research than the presentation of information about the research. Reason and emotion are interdependent and mutually influencing mental capacities. Some of this influence occurs outside of our conscious awareness, and it is not only negative but can be positive as well. Positive emotions such as joy and negative emotions such as fear are essential to planning and choosing in accord with one's short and long term best interests. It is thus misleading to think that people make purely cognitive decisions about participation in medical research solely on the basis of the medical information presented to them by researchers.

Whether a decision to participate in research is rational and meaningful for the subject is not determined by the information alone, but also by her unique cognitive/emotional response to it. This response may be influenced by social or familial factors. For example, an individual without medical insurance in the United States may enter a clinical trial believing that it is the only way to receive medical care. Also, parents of a terminally ill child with advanced cancer may feel obligated to do everything medically possible for their son or daughter. This may involve entering their child in a phase I oncology trial. Generally, the decision of a competent adult with a disease to enter a clinical trial is rational and meaningful for her when she believes and hopes that participating is in her best interests. These include not only her best medical interests, but also her best interests regarding her life as a whole. Moreover, participating may be rational and meaningful for her because she believes and hopes that it will lead to a cure for people who will be afflicted with her disease in the future. The interaction of beliefs and emotions is part and parcel of rational processing and decision making. Thus the presence of emotion as such in decision making does not necessarily refract the information conveyed to the subject to the point of misconstruing what is presented.

Still, the information may be misconstrued if the emotions are excessive and not in line with reasons for or against acting on the information. This may occur if the subject's positive emotions make him overly optimistic about a cure, and especially if the negative emotion of fear makes him desperate for one. What exacerbates this problem in phase I trials is that they are offered to people when all other treatment options have been exhausted. Excessive positive or negative emotions can distort rational judgment. In examining the psychological factors behind this misconception, it is important not to confuse the qualitative benefit that a participant might derive from believing that he is contributing to science with the qualitative benefit derived from believing that participation in a phase I trial will lead to a cure. Any qualitative benefit based on hope or desperation may very well be illusory. These types of cognitive/emotional states are largely responsible for the misconception many participants have about these trials.

The results of one study of the perceptions of cancer patients in a phase I oncology trial conducted by Charles Daugherty and colleagues at the University of Chicago are a good example of the therapeutic misconception. Thirty patients were surveyed. Although 93 per cent said they understood the information given to them, only 33 per cent were able to state that the purpose of the trial was to determine toxicity, tolerability, or the safest dose of the drug that was administered. Less than one third of the participants said the research team discussed the option of no treatment but supportive care with them. Only a few participants said they were motivated by altruism. Eighty five per cent said they had decided to participate for the reason of possible therapeutic benefit.⁷ This last fact by itself is not problematic. What is problematic is that there was no evidence that this majority of participants did any weighing of the potential benefits and risks of participating in the study. These results may be generalised to a larger number of research subjects in similar trials. They also underscore the obligation of researchers not to mislead subjects about potential benefits in these trials and instead to emphasise their non‐therapeutic purpose. Oncologist Matthew Miller spells out what this obligation entails:

We cannot continue to claim that, since the novel agents under investigation have never before been used in humans, any dose is potentially therapeutic. The opposite is true. Unless and until we know whether a given drug is effective, under what conditions, for which malignancies, and at what dose, these trials remain non‐therapeutic and ought to be spoken of as such.⁸

A fair and accurate presentation of information about a phase I anticancer drug trial must include mention of any efficacy in animal models and in vitro studies. It must also include data on response rates to anticancer drugs in human subjects. An adult participant or parent of a child may seize upon the mention of “efficacy” or “benefit” in the investigator's explanation and in the consent form, paying little or no attention to the “not likely” that may precede or follow it. This may be due to people's tendency to confuse a phase I trial with phase II and III trials, where research and therapy may overlap to some extent.⁹ Unlike early stage trials, subjects in more advanced trials may benefit from participating in them. What reinforces this confusion is the tendency among some subjects to perceive the researcher as a physician, as someone to whom they stand in a therapeutic relationship. They may identify the researcher as someone from whom they will receive medical care.

The misconception about efficacy may also be a reflection of the subject's belief in and hope of receiving a benefit. From a neutral third party perspective, the possible benefit may be negligible. Yet for the subject it may be significant, and participation in a trial on this basis cannot be dismissed out of hand as uninformed or irrational. The subject may believe that, for him or her, the possible benefit of participating in the trial, however slight, outweighs the risks. These risks include not only physiological side effects of drug toxicity, but also the emotional side effects of the defeat of hope for one last chance of remission or cure. These risks may be rational to take when one is facing imminent death. However, a rational therapeutic optimism consisting in weighing low probable benefit against risk should be distinguished from an irrational therapeutic misconception. In the latter, there is no careful weighing of low probable benefit against risk, but a belief in a direct benefit without much, if any, consideration of risk.

To be sure, researchers and clinicians should do more to encourage informed decision making among research subjects. We must not encourage flawed decisions simply because we humans continue to make them. In particular, we should try to limit the influence of negative emotions such as fear or desperation in subjects' decision making as much as possible. We must not, however, be misled into thinking that more careful presentation of information about research will eliminate the tendency among subjects to conflate research and therapy. Informed consent is an imperfect process of communication between researchers and subjects involving more than a value neutral presentation and explanation of medical information. It also involves a value laden interpretation of that information by subjects in virtue of their cognitive/emotional state of mind, which can be and often is influenced by their unique personal situation.

Admittedly, if more potential subjects clearly distinguished between research and therapy and believed that the probable benefit from research was low or negligible, then this might adversely affect the motivation for participation in clinical trials. The consequence of this for phase I oncology trials could be significant, as there could be a reduction in the number of people entering these trials. This in turn could have a negative impact on the development of more effective and safer drugs and procedures, since the multistage process necessary to test the safety and efficacy of experimental treatments might be pre‐empted from the start. Studies like the one conducted by Daugherty et al suggest that only a small percentage of research subjects are motivated by altruism to participate in phase I trials.¹⁰ Many are motivated by emotions such as fear of dying and hope of a remission or cure. This phenomenon may allay concerns about ensuring adequate enrolment in clinical trials. But it clearly would not be the most desirable way of achieving this goal if the emotions involved in one's decision to participate in a trial were based largely on an illusory sense of benefit.

One promising strategy for improving participants' understanding of research is to have a study team member or a neutral educator spend more time explaining the design and purpose of the research with each potential participant.¹¹ This could include testing subjects' comprehension during the informed consent process. Yet even if researchers did more to discourage the therapeutic misconception, many subjects would continue to think of clinical trials as therapeutic and would continue to participate on this ground. The subjective and situational aspects underlying this thinking and the reasons for participation cannot be factored out of the decision making process. So the possibility of a substantial reduction in the number of people entering trials is not likely to be realised.

Alternatively, researchers could tolerate the therapeutic misconception for the pragmatic reason of ensuring adequate enrolment in clinical trials. This second option is more ethically objectionable than the first. By focusing only on the goal of adequate enrolment, researchers would be disingenuous in explaining the reasons for participating in the research and in trying to persuade potential subjects to participate. This pragmatic option would be ethically indefensible if it amounted to encouraging people to take risks of physiological and psychological harm when they have false beliefs about the effects of an experimental agent.

A third option would be to pay people to participate in clinical trials. This might send the message that they were participating in these trials for the sake of science and should be compensated for it, which would not occur if they were acting because they expected to benefit from it.¹² Some might question this remunerative option, arguing that it could result in payment being a coercive offer to a vulnerable patient population such as the poor or uninsured. It could be an incentive to take risks in exchange for money. This would not necessarily follow, though. As Christine Grady points out, an amount of money that is not excessive and is calculated on the basis of time and contribution would not constitute an undue inducement.¹³ Instead, it would show respect for the contribution that subjects make to research and to the common good.¹⁴ Nevertheless, this option at best would ameliorate but not resolve the problem of misperception about research.

In recruiting subjects for a phase I oncology clinical trial, researchers are obligated to explain the design and purpose of the trial to them as clearly and carefully as possible. This includes trying to dispel any perceived or apparent misconception people might have about the trial. Consent forms must also explicitly state the design and goals of the trial, as well as the potential benefits and risks. These forms should also include data on response rates and adverse events. Although the efforts of researchers may lower the incidence of the therapeutic misconception among research subjects, many subjects will continue to believe they can benefit from participating in clinical trials. Certain emotions and other psychological features of the thought processes of subjects will remain beyond the control of researchers, regardless of the steps they may take to try to dispel any misconception about research. So the problem will not likely be eliminated. In many cases, the therapeutic misconception may be an unavoidable part of the imperfect process of recruitment and consent in medical research.