A paper I wrote regarding therapeutic misconception and clinical research in oncology.

1. Oncologic Misconception 1
Running head: THERAPEUTIC MISCONCEPTION IN ONCOLOGY RESEARCH
Therapeutic Misconception in Oncologic Clinical Research:
An Overview
Kellie L. Bodeker
George Washington University
I, Kellie L. Bodeker, affirm that I have completed this assignment/examination in
accordance with the Code of Academic Integrity

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Abstract
Therapeutic misconception, the belief by research subjects that a clinical trial will
provide direct benefit to them, was described by Appelbaum, Roth, and Lidz in 1982.
Life-threatening illnesses, such as cancer, present a unique challenge to clinical
research. Placebo studies are clearly unethical. Comparator studies (phase III) of a new
drug against a proven regimen are also a concern, yet essential for the progress of
oncologic therapy. An essential understanding of purpose, benefit, and risk is critical for
solid informed consent. Herein, a review of therapeutic misconception in oncologic
research is undertaken. Recommendations are made to reduce incidence of
misconception and increase realistic expectations from the clinical trial.

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Therapeutic Misconception in Oncologic Clinical Research: An Overview
Introduction
In 1982, Appelbaum and colleagues introduced the concept of therapeutic
misconception, defining it as “…research subjects will assume (especially, but not
exclusively, in therapeutic research) that decisions about their care are being made
solely with their benefit in mind.” (Appelbaum, Roth, & Lidz, 1982, p. 321) This presents
a problem for the clinical research in a therapeutic setting if the study, indeed, does not
represent the best interests for the potential subject (e.g. placebo). Therefore, the
physician investigator is put into an ethical conflict between the good for society (the
research) and the good for the individual (the patient).
This ethical paradox is more heightened in the case of oncologic research. While
not defined as a vulnerable population, cancer patients (or any other patient with a life-
threatening illness) have a unique desperation contrasted to otherwise benign disease.
These patients are typically inundated with information after a devastating diagnosis,
after which only approximately 50% of the information is recalled (Jansen, et al., 2008).
While the authors stated age was an influencing factor, the more significant concerns
were the seriousness of the diagnosis/prognosis and associated expected life
expectancy. Any information presented after such news was, the authors postulated,
poorly absorbed at best.
This presents a unique twist to the already confounding factor of therapeutic
misconception. Cancer research follows the accepted, generalized format of phase I
(safety and maximum tolerated dose), phase II (most efficacious dose), and phase III
(comparative outcomes). A safety net, of sorts, is incorporated by having initial phase I

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studies recruit patients who are treatment refractory to standard therapies. Phase II
studies, however, present more of a therapeutic challenge, as they may utilize patients
who would otherwise benefit from an established treatment regimen. If this challenge is
not presented in a phase II study, it becomes problematic with the phase III design for
therapeutic outcomes. When asking a potential subject to participate in a clinical trial
that would ask the patient to not utilize proven therapies, informed consent is of
heightened criticality. Perhaps for this reason, a significant undertaking has occurred
regarding informed consent, therapeutic misconception, and clinical equipoise in the
oncologic realm.
Literature Review
To further define and evaluate therapeutic misconception, Appelbaum et al
(1982) performed case studies on two psychiatric research studies. Subject consents
were videotaped and, shortly after consent, the subjects underwent a structured
interview regarding their observations and opinions of the consent process. Subjects
were also reinterviewed two weeks later.
The two psychiatric studies were described as Project A (n=13) , involving social
skill training on chronic schizophrenics, and Project B (n=18), involving a comparator
study for a personality disorder medication. Both groups utilized placebo (or no
treatment) cohorts. Randomization was employed in both studies; Project B employed a
double-blind methodology.
The studies had variations in consent techniques. Project A utilized an informed
consent document (ICF) that did not explain how the cohort assignment would be
determined. Additionally, this information was commonly not provided during the oral

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consent procedure. In contrast, Project B participants “…underwent a nearly ideal
consent process.” (p. 323). Not only was the randomization described in the ICF, but the
investigators met with potential subjects for a significant length of time, describing in
detail the process.
Interviews after the consent process revealed 46% of Project A did not know how
they would be assigned to their cohort. Of the remaining 54%, none of the subjects
answered correctly as to how the cohort would be assigned. Of the Project B subjects,
55% did not understand how their cohort would be assigned to them.
These results are echoed somewhat in a study done by Dougherty et al
(Daugherty, et al., 1998). This study sought to empower treatment-refractory cancer
patients during a phase I process, utilizing a 3-step consent process designed to educate
patients about chemotherapy and their treatment options. Twenty four of the twenty
nine subjects agreed to participate in the consent evaluation correlative portion to this
phase I study. The control population was then selected from subjects enrolled in other
therapeutic phase I trials and matched for age, sex, and education.
Sixty-one percent of the ‘consent’ cohort stated to understand all of the consent
document, with another 35% understanding most of it. In contrast, 38% of the control
population stated they understood all of the consent document, with 62% understanding
most. Forty-eight percent of the ‘consent’ cohort could truly define the purpose of the
phase I study (i.e. safety) whereas only 29% could in the control group. Fifty-two
percent of the ‘consent’ cohort and 71% of the control group believed the phase I study
was designed to determine efficacy or produce a remission/cure. Fifty-seven percent

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and 62% of the ‘consent’ and control cohorts, respectively, stated their primary goal for
enrolling in the phase I study was to obtain a cure. (Daugherty, et al., 1998)
Similar findings were presented by Daughtery in a more robust study of 61
institutions and 1,000 research subjects. Subjects were sent a survey regarding their
participation in recent clinical trials (Daugherty, 1999). Of these, 85 % of the subjects
stated they had enrolled in the phase I study to obtain possible therapeutic benefit and
only 33% could state the purpose behind the study. These results were echoed by Nurgat,
who found 89% of subjects participated for a benefit to self (Nurgat, et al., 2005).
Joffee et al reviewed 73 clinical trials, of which approximately 25% were phase I
and 50% phase II, with the remaining phase III (Joffe, Cook, Cleary, Clark, & Weeks,
2001). Of these trials, about 28% of the subjects had signed consent at the first
discussion and 43-49% had consulted other information regarding the research trial.
About 87% believed the informed consent document was easy to understand.
When questioned regarding the study the (phase I) study they participated in, the
subjects replied that all the treatments had been standard (48%), that the research
treatment was the best possible treatment available (29%), and there were no additional
risks or discomforts due to the research trial (38%). All of these beliefs are, in fact,
erroneous and idealistically should have had a low response rate. Additionally, 16%
responded that they believed they would have a direct benefit from participating in the
phase I clinical study.

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Discussion
Appelbaum and colleagues investigated informed consent techniques, varying
both the printed document and the process (i.e., conversation and interaction)
(Appelbaum, et al., 1982). Despite enhanced consenting techniques, describing Project
B’s as ‘ideal,’ therapeutic misconception was still rife within both groups. The authors
state that research subjects from both groups A and B created explanations as to how
treatments would be assigned. While it could be understood why subjects from Project A
created an explanation (because randomization was not explained to them or provided
on the ICF), subjects from Project B (55%) also created scenarios despite a robust
consent. Indeed, one subject became upset after discovering he had received placebo,
only to state that he would not have participated if he knew he would not have
consented (Appelbaum, et al., 1982, p. 324).
The capacity for suspension of rationalization is epitomized in case example 3 of
Appelbaum et al. (1982, p. 327):
Subject was a 25 year old woman with three years of college...participating
in Project B…understanding of the research was generally excellent…
spontaneously described the three groups, including the placebo group, and
indicated that assignment would be random…and that a double blind would
be used. When she was asked directly, however, how her medication would
be selected, she said she had no idea. She then added, “I hope it isn’t by
chance,”….She was asked what her understanding of “random” was. Her
definition was entirely appropriate: “By lottery, by chance, one patient who
comes in gets one thing and the next patient gets the next thing.” She then

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began to wonder out loud if this procedure were being used in the current
study. Ultimately, she concluded that it was not. (p. 327)
This quote from Appelbaum et al provides insight to a problem that is echoed in
the other literature. Dougherty (1998) noted that cancer patients with treatment
refractory disease may ignore or pay less attention to discomfort, harm, or risk
statements within the informed consent or dialogue if they believe the trial may provide
a therapeutic expectation. An additional conclusion was that a heavy disease burden,
poor prognosis, or desire for results also fosters therapeutic misconception. Thus, if
cancer patients are unreceptive to the truth, this presents an additional quagmire to a
truly robust consent process for oncologic research.
Daughtery noted that a static consent form, or process, would not facilitate an
ethically robust consent to overcome this problem. One suggestion to help reduce
consent problems was to employ a cohort specific consent, with a unique consent
document created for each study arm. Each document would have specifically
tailored risks and discomforts, aiding readability. Unfortunately, as the authors note,
the complexity of the study may preclude this or render it a difficult task. A double
blind technique, for example, or a gated study where the subjects are repeatedly
randomized based on progress (e.g. Children’s Oncology Group AALL0331) would
negate this possibility.
Emphasizing lack of benefit to self, and focusing on benefit to society/others,
could also help reduce therapeutic misconception. Daughtery concluded that altruism
plays a very low role in motivation behind research participation. This was echoed by

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Nugart. This also presents a problem, as a significant amount of cancer research is based
on a societal benefit, and not a benefit to the individual participant.
Area for Change
Appelbaum et al state that some researchers argue “…subjects could not
comprehend or utilize the information researchers were now obliged to disclose.”
(Appelbaum, et al., 1982, p. 319). A field such as cancer research, mired in cytotoxins,
immunobiologics, and radiation therapies, could provide an easy basis for such
rationalization. However, the ethical principles of autonomy require researchers to
respect each individual to make an informed decision regarding their care. For this
reason, each potential subject must be well educated regarding not only the research
presented, but the basic principles of therapy.
An article by Kass and colleagues explored a mechanism for better educating
research subjects regarding clinical trials and expectations (Kass, et al., 2009). The
researchers studied a multi-media (i.e., computer based), patient-interactive
presentation for consent that was tailored to phase I-III, cancer research trials. The
control group was given a NCI-generated pamphlet that did include post-marketing
studies. Subjects were given this information prior to meeting with their oncologist to
discuss potential study participation; information was reviewed privately. Of the 288
participants who were randomized to receive the different media interventions before
recruitment, 130 completed the survey about the potential study. Seventy received the
multi-media presentation and 60 were assigned to the control.
Approximately twice as many subjects who reviewed the multi-media
presentation could define the true intent of a phase I study compared to the control

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group (p = 0.03). Unfortunately, the numbers are low: 34% for the intervention and
16% for control. This means 66% of the intervention (i.e. multimedia) cohort could not
accurately convey the true purpose behind the phase I study to which they consented.
Indeed, 25% of those utilizing the computer-based presentation stated the purpose of
the investigational study was to “see if the drug will help me,” (p. 8, table 1) with an
additional 17% stating “to cure my cancer.” The respondents from the control group
(NCI-pamphlet) had a proportion of 29% and 13%, respectively, to the same statements
This recent study by Kass and colleagues is more concerning than those
mentioned prior, for the simple fact the survey is contained within the article. Whilst
others have also utilized a survey mechanism to evaluate the efficacy of consent and/or
therapeutic misconception, these tools have not been documented within the papers
(Appelbaum, et al., 1982; Daugherty, et al., 1998; Nurgat, et al., 2005). This becomes a
critical concern due to the framing of the questions. Kass et al state specifically on their
questionnaire, “What do you think is the purpose of the investigational study?”
[emphasis added] (p. 8, table 1). This clearly calls out for the subject to define the
study’s purpose. Alternatively, a poorly framed question could be “What is the function
of this study?” or “What was the reason behind this study?” Such poorly worded
questions could confuse the scientific purpose with the subject’s own reasons for
enrolling in the clinical trial. Specifically, the subject’s own personal desires or hopes
versus the truisms of research.
This, then, also becomes an issue for clinical cancer researchers. In order to
obtain a robust consent for a therapeutic oncologic trial must the subject’s hopes be
crushed? Does informed consent mean conformity? Subjects responding to Kass et al’s

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survey seemed to have more hope. 36% of the intervention respondents and 8.3 of the
control respondents believed those individuals who did not participate in research were
likely to have their cancer get worse or remain static. In contrast, 4.3% of the
intervention respondents believed those who participated in the research were likely to
have their cancer get worse or remain static and 0% (no respondents) from the control
group believed this. Is this a sign of misunderstanding or a sign of hope in a world of
bleak treatment options?
Conclusion
Therapeutic misconception has become somewhat synonymous with poorly
performed consent. This was echoed by Sugarman et al, who found a inverse
relationship between robustness of consent and therapeutic misconception (Sugarman,
et al., 2005). However, when evaluating cancer patients for therapeutic misconception,
the survey tool must be written to specifically query the objective of the study versus the
perceived purpose. Additionally, despite robust consent and knowledge, cancer patients
on a research study may be in denial regarding the details and specifics that directly
affect them. This presents a two-fold problem: (a) the subjects may seem adequately
consented, yet not internalize their own risk, and (b) there are no current consenting
techniques to adapt and correct this problem. Further discussion amongst experts is
needed to determine when a subject’s consent ends and personal expectations (hope)
begins and, if necessary, research methodology to determine its causal link to
misconception.

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References
Appelbaum, P. S., Roth, L. H., & Lidz, C. (1982). The therapeutic misconception:
informed consent in psychiatric research. Int J Law Psychiatry, 5(3-4), 319-329.
Daugherty, C. K. (1999). Impact of therapeutic research on informed consent and the
ethics of clinical trials: a medical oncology perspective. J Clin Oncol, 17(5), 1601-
1617.
Daugherty, C. K., Ratain, M. J., Minami, H., Banik, D. M., Vogelzang, N. J., Stadler, W.
M., et al. (1998). Study of cohort-specific consent and patient control in phase I
cancer trials. J Clin Oncol, 16(7), 2305-2312.
Jansen, J., Butow, P. N., van Weert, J. C., van Dulmen, S., Devine, R. J., Heeren, T. J., et
al. (2008). Does age really matter? Recall of information presented to newly
referred patients with cancer. J Clin Oncol, 26(33), 5450-5457.
Joffe, S., Cook, E. F., Cleary, P. D., Clark, J. W., & Weeks, J. C. (2001). Quality of
informed consent in cancer clinical trials: a cross-sectional survey. Lancet,
358(9295), 1772-1777.
Kass, N. E., Sugarman, J., Medley, A. M., Fogarty, L. A., Taylor, H. A., Daugherty, C. K.,
et al. (2009). An intervention to improve cancer patients' understanding of early-
phase clinical trials. IRB, 31(3), 1-10.
Nurgat, Z. A., Craig, W., Campbell, N. C., Bissett, J. D., Cassidy, J., & Nicolson, M. C.
(2005). Patient motivations surrounding participation in phase I and phase II
clinical trials of cancer chemotherapy. Br J Cancer, 92(6), 1001-1005.

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Sugarman, J., Lavori, P. W., Boeger, M., Cain, C., Edsond, R., Morrison, V., et al. (2005).
Evaluating the quality of informed consent. Clin Trials, 2(1), 34-41.