Therapeutic Misconception in Oncologic Research


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Therapeutic Misconception in Oncologic Research

  1. 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
  2. 2. Oncologic Misconception 2 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.
  3. 3. Oncologic Misconception 3 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
  4. 4. Oncologic Misconception 4 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
  5. 5. Oncologic Misconception 5 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
  6. 6. Oncologic Misconception 6 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.
  7. 7. Oncologic Misconception 7 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
  8. 8. Oncologic Misconception 8 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
  9. 9. Oncologic Misconception 9 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
  10. 10. Oncologic Misconception 10 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
  11. 11. Oncologic Misconception 11 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.
  12. 12. Oncologic Misconception 12 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.
  13. 13. Oncologic Misconception 13 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.