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Are therapeutic motivation and having one's own doctor as researcher sources of therapeutic misconception?
  1. Scott Y H Kim1,2,
  2. Raymond De Vries2,3,
  3. Sonali Parnami2,
  4. Renee Wilson4,
  5. H Myra Kim5,
  6. Samuel Frank6,
  7. Robert G Holloway7,8,
  8. Karl Kieburtz4,7,9
  1. 1Department of Bioethics, National Institutes of Health, Bethesda, Maryland, USA
  2. 2Center for Bioethics and Social Sciences in Medicine, University of Michigan, Ann Arbor, Michigan, USA
  3. 3Department of Medical Education, University of Michigan, Ann Arbor, Michigan, USA
  4. 4Center for Human Experimental Therapeutics, University of Rochester, Rochester, New York, USA
  5. 5Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA
  6. 6Department of Neurology, Boston University, Boston, Massachusetts, USA
  7. 7Department of Neurology, University of Rochester, Rochester, New York, USA
  8. 8Department of Community and Preventive Medicine, University of Rochester, Rochester, New York, USA
  9. 9Department of Environmental Medicine, University of Rochester, Rochester, New York, USA
  1. Correspondence to Dr Scott Kim, Department of Bioethics, National Institutes of Health, 10 Center Drive, 1C118, Bethesda, MD 20892-1156, USA; scott.kim{at}nih.gov

Abstract

Background Desire for improvement in one's illness and having one's own doctor functioning as a researcher are thought to promote therapeutic misconception (TM), a phenomenon in which research subjects are said to conflate research with treatment.

Purpose To examine whether subjects’ therapeutic motivation and own doctor functioning as researcher are associated with TM.

Methods We interviewed 90 persons with advanced Parkinson's disease (PD) enrolled or intending to enrol in sham surgery controlled neurosurgical trials, using qualitative interviews. Subjects were compared by motivation (primarily therapeutic vs primarily altruistic or dually motivated by altruistic and therapeutic motivation), and by doctor status (own doctor as site investigator vs not) on the following: understanding of purpose of study; understanding of research procedures; perception of chance of direct benefit; and recollection and perceptions concerning the risks.

Results 60% had primarily therapeutic motivation and 44% had their own doctor as the site investigator, but neither were generally associated with increased TM responses. Overall level of understanding of purpose and procedures of research were high. Subjects responded with generally high estimates of probability of direct benefit, but their rationales were personal and complex. The therapeutic-motivation group was more sensitive to risks. Five (5.6%) subjects provided incorrect answers to the question about purpose of research, and yet, showed excellent understanding of research procedures.

Conclusions In persons with PD involved in sham surgery clinical trials, being primarily motivated by desire for direct benefit to one's illness or having one's own doctor as the site investigator were not associated with greater TM responses.

  • Research Ethics
  • Gene Therapy/Transfer
  • Clinical trials
  • Decision-making
  • Policy Guidelines/Inst. Review Boards/Review Cttes.

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Introduction

One of the most prominent constructs used to examine the adequacy of informed consent is the concept of therapeutic misconception (TM), a phenomenon in which research subjects are said to conflate research with treatment.1 This may manifest in subjects’ misunderstanding the purpose of research, failing to understand that research procedures are not individualised to them, and harbouring false beliefs about the risks and benefits of participation. The prevalence of TM is reported to be high,2–5 and some authors refer to the ‘ubiquity’ of TM.6 In terms of causes of TM, there are two factors that are often mentioned as likely sources: the research subject's motivation for direct personal benefit1 ,4 and the involvement of the subject's own physician as the researcher.1 ,7

Despite some claims of high prevalence of TM-related phenomena that are based on analysis of very few closed-ended questions,4 ,5 ,8 TM does not have a widely accepted definition and lacks an accepted operationalisation for research.9 Our approach has been to use a mixed methods framework to examine TM-related phenomena by attempting to understand how research subjects make their research participation decisions.10–12 Our subjects are persons with advanced Parkinson's disease (PD) involved in sham surgery trials. This is a particularly good setting to study TM because of the seriousness of the illness, the lack of disease-altering or curing treatments for PD, and the nature of the intervention (neurosurgery) that is very rarely an experimental procedure—all of these factors should, in theory, promote a therapeutic mindset in the subjects.

We report here the relationship between, on the one hand, the two potential sources of TM (subject's motivation for direct personal benefit and the involvement of subject's own physician as the researcher) and, on the other, the most often discussed loci of TM-related phenomena: the subjects’ understanding of the purpose of research; their understanding of the extent to which the procedures would be individualised to their needs; their beliefs and expectations concerning the chance of direct benefit; and their recollection and perceptions concerning the risks involved in the research.

Methods

Participants

Participants were 90 individuals from three sham surgery-controlled intervention trials for PD. The participants were asked by the parent study staff if they were willing to be contacted by our study team for this interview study. The subjects who agreed to be contacted were then recruited and interviewed by phone. In the ‘GAD study,’ participants were individuals considering enrolment in a study evaluating glutamic acid decarboxylase gene transfer in subjects with advanced PD, sponsored by Neurologix.13 Subjects were randomised at a 1:1 ratio to receive either injections of the study agent or sham surgery placebo, which involved partial thickness burr holes with injection of saline under the skin. The trial assessed 66 individuals for eligibility across seven sites. We recruited from five of the seven sites and conducted interviews with 29 of 45 (64.4%) subjects evaluated for enrolment at those sites. Although our goal was to interview everyone prior to surgery, five subjects were interviewed after their surgery due to scheduling difficulties. Five additional subjects were found to be ineligible following screening and one subject ultimately declined participation after screening; however, their interviews were conducted at a time when they were actively considering participation in the trial. Thus, they are included in this report.

The subjects from the second (STEPS trial) and third trials (CERE-120 trial) were interviewed retrospectively. The STEPS trial tested human retinal pigmented epithelial cells which secrete dopamine.14 Sham surgery involved partial thickness burr holes. The trial enrolled 71 subjects at 10 sites. We recruited from five sites, interviewing 55% (31/56) of enrollees at those sites. The CERE-120 trial tested the gene for neurotrophic factor neurturin.15 Sham surgery involved partial thickness burr holes. We recruited from seven of the nine study sites, interviewing 70% (30/43) of enrollees. Due to sponsor requests, the time point of interviews differed between these latter two trials. CERE-120 enrollees were approached for interviews approximately 1 month after surgery. Twenty-six (86.7%) enrollee interviews took place between 1 and 9 months after their surgery. STEPS enrolees were approached after the blind in the trial had been broken. Thus, for the STEPS trial, 7 (22.6%) interviews occurred less than 2 years postsurgery, 10 (32.3%) interviews between 2 and 4 years after surgery and 14 (45.2%) occurred greater than 4 years postsurgery.

All interviews were conducted via telephone and were recorded and transcribed. Interviewer notes were used for one interview because of technical difficulties in recording.

The institutional review boards of the University of Rochester and the University of Michigan reviewed the study and deemed this study exempt from US federal regulations.

Measures

Conditional Probe Interview (CPI). The CPI is a semistructured qualitative interview guide designed to elicit how the subjects made their decisions about participation.16 It places a strong emphasis on allowing the subject to follow his/her own narrative in eliciting a chronological description of how the subject came to make his/her decision. The instructions emphasise that the interview is designed to be ‘qualitative and subject oriented, so the interview should remain flexible enough to allow the subject to speak openly and share information that is important to him/her.’ More detailed description of the CPI can be found elsewhere.16 This paper focuses on those questions in the CPI that specifically address motivation, MD status and TM-related phenomena.

Demographic and clinical background information. Basic demographic information (age, gender, education, race and ethnicity, marital status, employment status) and information on the subject's PD status were collected (number of years since diagnosis).

Analysis

After all transcriptions were checked for accuracy, two research assistants read through the transcripts and developed a provisional coding scheme by adapting the coding framework used in a previous study.16 These codes were further refined in meetings involving two of the investigators (SYHK and RDV). The two assistants then independently coded each transcript using the coding scheme. Any coding discrepancies were discussed until a consensus was reached; if the two coders could not reach a consensus, the discrepancies were brought to a weekly meeting with the two investigators and resolved by discussion. Through this iterative process, the team ensured the coding scheme was open to change and refinement, and allowed the team to capture new and unanticipated themes. To prevent drift in coding, 10% of the transcripts were also coded independently by two investigators (SYHK and RDV).

The analysis was then organised around responses to the following question about motivation: ‘What is your main reason for participating in the (study name)?’ (hereafter referred to as the motivation question) and a question about whether one's own neurologist was also the site investigator: ‘Is your regular doctor (the person who treated you before the study) also the (site investigator)?’ (doctor status question). We divided the subjects into those who stated only direct personal benefit motivation versus those who stated only altruistic motivation, or personal benefit and altruistic motivations. This was done because having an altruistic motivation (even if in addition to a therapeutic motivation) suggests that the subject understands that at least one purpose of research is to benefit others and, thus, persons expressing such a motivation (even if they also express a therapeutic motivation) may be distinct from those who mention only therapeutic motivation.

We examined the differences in the distribution of various measures by motivation and by doctor status using cross tabulations with variables of primary interest (eg, understanding purpose of study, study design, etc) using Fisher's exact tests.

Results

The subjects’ motivations for participation in their clinical trials are shown in table 1. Sixty percent responded only with personal benefit as their motivation for participation; the remainder expressed altruistic or dual motivation. Almost half (44.3%) the subjects reported that their regular neurologist was also the site investigator. Among subjects with own doctor as site investigator, half (51%) mentioned only direct personal benefit as their motivation, compared with 68% of those with site investigators who were not their own doctors (Fisher's exact test, p=0.19). The subjects’ characteristics according to their motivation, and whether their own doctor (own doctor vs other) was the site investigator revealed no significant differences (table 2).

Table 1

Motivation for participation (n=90)

Table 2

Comparison of subject characteristics by motivation and by doctor status

Understanding of purpose of research

Five subjects (9.3%) in the direct personal benefit motivation group stated that the clinical trial is primarily intended to help the study participants, whereas none of the altruism/dual motivation group gave that response; none of these five subjects were from the group with their own doctors as site investigators. (We separately examined the understanding of research procedures and design in these five subjects; see below). Also, although we asked the subjects to name the ‘primary’ purpose, some subjects resisted expressing a priority and said that the purpose was ‘both’ to help future patients and to help the participants (or to increase knowledge). (table 3)

Table 3

Comparison of subjects’ understanding of purpose of research by motivation and doctor status

Understanding of research procedures and design

Overall, large majorities correctly answered questions regarding method of arm assignment, randomisation probabilities, purpose of sham surgery arm, and the difference in procedures between the two arms (table 4).

Table 4

Comparison of subjects’ understanding of research procedures and design, by motivation and doctor status

There were no significant differences by motivation or by doctor status. Of note, when asked about the purpose of the sham surgery arm, 68% (36/53) of subjects with only direct personal benefit motivation versus 54% (19/35) of altruism/dual motivation subjects specifically mentioned the need to control for the placebo effect, although the difference was not significant (p=0.08).

We examined whether the five subjects (from table 3) who incorrectly said that the purpose of the clinical trial is primarily to benefit the participants also lacked understanding of study procedures. Despite their incorrect answer to the purpose question, all five subjects correctly stated the purpose of sham arm (4 specifically mentioning the placebo effect) and described the differences between two arms accurately. Only one person gave an incorrect probability of placebo assignment (‘I think it was 1 in 8…’) and one subject was ‘unsure’ of method of arm assignment. Thus, 18 of 20 understanding questions (5 subjects×4 questions) were answered correctly.

Perception of, and attitudes toward, potential benefits and risks

In regard to perception of likelihood of personal benefits, subjects generally gave an optimistic answer with fewer than a quarter of the subjects saying there was very low or modest chance of benefit, with no significant difference by motivation or by doctor status (table 5).

Table 5

Comparison of subjects’ perception of potential direct benefit and reported bases for that perception, by motivation and doctor status

The subjects’ statements regarding likelihood of direct personal benefit were probed with follow-up questions (table 5). When asked about the basis for the belief concerning the chance of benefit, a variety of answers were given. The most common response referred to information connected to the phase 1 study (whether disclosed by the study or found on their own from other sources). When asked if their belief regarding chance for direct personal benefit was based on something that was disclosed to them, most subjects replied in the negative. However, greater proportion of direct personal benefit motivation subjects than altruism/dual motivation subjects said it was (25% (13/53) vs 6% (2/34), p=0.04), while the doctor status variable was not associated with the response.

When the subjects were asked about what the researchers or the informed consent form stated regarding chance of benefit, persons in the direct personal motivation group were more likely to say that researchers were negative about likelihood of direct benefit (16% vs 7% in the altruism/dual motivation group) but also that researchers were positive about direct benefit (21% vs 3% in the altruism/dual motivation group), whereas, persons in the altruism/dual motivation group were more likely to say that researchers did not give specific or general indication regarding direct personal benefit (79% vs 52% in the direct personal benefit group). These results, however, were not statistically significant (Fisher's exact test, p=0.08) (table 5).

In terms of risks, a majority of the subjects (approximately 58% of the entire group) recalled risks associated with the surgery and the experimental treatment (ie, gene insertion or cell transplant), and this did not vary significantly by motivation or doctor status (table 6).

Table 6

Comparison of recollection and perception of risks, by motivation and doctor status

But a sizable minority (37%) recalled only risks of surgery or only risks of the experimental treatment. In terms of perception of probability of harm, a large majority (83%) of subjects responded that there was no, very low, or modest chance of experiencing adverse events. If subjects are compared by no/very low chance of risk versus all other responses, it appears that a higher proportion of the altruism/dual motivation group perceived low probability of risk than the direct personal benefit group (82% vs 60% responding no/very low chance, p=0.03), and a higher proportion of the own doctor group perceived low probability of risk (81% vs 60%, p=0.06) (table 6).

Discussion

Research participants’ motivation for direct personal benefit1 ,4 and the involvement of their own doctors as researchers are perhaps the two most discussed potential sources of the TM.1 ,7 In our study, whether one had primarily a personal benefit motivation versus an altruistic or dual motivation was not associated with TM-related phenomena. The two groups’ understanding of the purpose of research was similar. Although 5 (9.3%) in the personal benefit group incorrectly stated that the study was primarily intended to help those participating, those five subjects’ specific understanding of arm assignment, randomisation probability, rationale for sham arm, and difference in procedures between two arms was excellent, with only one instance of an incorrect answer and one ‘not sure’ answer (out of 20 opportunities, ie, 5 subjects×4 questions). The direct personal benefit group and the altruism/dual motivation group showed no differences in understanding of various research design elements, in perception of direct benefit, and in recollection of research risks. Both groups were also quite optimistic in their replies to likelihood of personal benefit, but the overwhelming majority in both groups said this was not based on what they were told by the researchers or the informed consent form; instead, the participants cited as bases for their views of potential benefits a variety of personal interpretations and reasons.

The altruism/dual motivation group was more likely to perceive no or very low chance of risk (82% vs 60% in direct personal benefit group). Thus, being motivated solely by desire for therapeutic benefit does not seem to lower or dampen perception of risk. In fact, it may be that therapeutic motivation as part of an overall regard for one's welfare may, rather than blinding one to the dangers of research (out of desperation), make someone more likely to pay attention to the risks of research as a matter of guarding or promoting one's own welfare.

What was the effect of having one's own doctor as the site investigator? One might expect persons whose own doctors were also the site investigators to have more of a therapeutic motivation, since they would have been more likely to see the research participation as receiving treatment from their own doctor. This was not the case. Instead, although the difference (51% of own doctor group had primarily therapeutic motivation vs 68% of those whose site PI was not their own doctor) was not statistically significant, the direction of the effect was opposite of expected. None of the five subjects who stated that the research was primarily intended to help the subjects of the study were in the own doctor group.

Further, the doctor status variable was not associated with differences in understanding of procedures or in perceptions and expectations of benefits and recollection of risks. The own doctor group had a higher proportion (81% vs 60%) of subjects who said there was no or very low chance of adverse events.

These results regarding the doctor status are generally not consistent with the traditional TM interpretation which says that having one's own doctor as the site investigator will blur the line between research and treatment, leading to TM. Instead, it appears that those who do not have their own doctor as the site investigator (ie, those who seek out research opportunities of their own initiative) are more likely to be concerned about potential direct benefit from research (and perhaps more concerned about risks as well, as a matter of an overall concern for their own welfare). By contrast, when patients are recruited by their own doctors—patients who may not have been actively ‘looking for research’—there may be a greater prevalence of altruistic motivation (although in this small sample study, the difference was not statistically significant). They may also be less concerned about risks, perhaps, we speculate, due to a greater trust in the researcher who is their own doctor.

We highlight three ethical implications of our findings. First, our results reinforce the need to distinguish between motivation and understanding in the ethical assessment of informed consent. Consistent with previous studies,4 ,16 ,17 we saw that research participants understand the purpose of research and its various elements regardless of their motivation for participation. As others have noted, it is important not to assume that being motivated by a desire for benefit implies a faulty understanding of research17 ,18—just as one can rationally buy a lottery ticket desiring to win, all the while understanding that a lottery’s purpose is not to enrich the buyer of tickets, but rather to raise funds.

Second, the traditional TM framework makes empirical assumptions that may not be warranted. For example, it focuses on the potential that therapeutic motivation will blind subjects’ understanding of research purpose, design, benefits and risks. But this ignores the self-protective function of self-interest which may, in fact, enhance understanding (eg, understanding the scientific rationale for the sham design) or heighten sensitivity to risks.

In fact, based on our results, some may even ask if it is those with altruistic motivation who need special protections, if their motivation leads to decreased sensitivity to risks. Our sense from the data is that there is not a need for special protections. The personal benefit group and the dual/altruism group had good understanding of the purpose and design of their clinical trials, and the two groups did not differ on their recollection of research risks. It is also arguable as to which group is ‘more accurate’ regarding their perception of likelihood of adverse events. That is, ‘very low’ chance and ‘modest’ chance could imply similar numerical probabilities for different people, and we do not have an objectively ‘correct’ answer to the perception of risk question. However, the potential divergence on perception of risks based on motivation for research participation does suggest that in enrolling subjects into clinical research, we should not assume altruistically motivated subjects are immune to potential misperceptions. Perhaps learning of a subject's altruism should alert the person obtaining informed consent to especially focus on the risks and burdens of participation.

Third, another unexpected finding of this study raises questions about how we assess subjects’ understanding of purpose of research—the jumping-off point of all discussions about the TM.9 Our study revealed unexpected complexity on this issue. Even when asked specifically: ‘Is the primary goal to benefit the subjects participating in the study, or future PD patients?’ some insisted on endorsing both purposes—the correctness of which is unsettled even among experts in research ethics.9 Curiously, the five people who clearly stated the wrong answer showed nearly perfect understanding of all the dimensions of research design having to do with lack of individualised treatment in research; this casts considerable doubt on whether we should interpret their ‘incorrect’ responses as an indication that they truly believe that research is being conducted primarily as a form of treatment for them (as would be interpreted by standard TM view).

This study has several limitations. First, the sample size was quite modest, and for the qualitative questions, we were able to conduct only posthoc statistical tests. However, a highly powered comparison of groups (which generally requires large samples) within sham surgery trials in PD is quite unlikely given the usual small sample sizes of such studies, and our results which combined several such studies may represent the limit of what is feasible. Second, qualitative research involves interpretive judgments in development of coding schemes and in the coding itself. Third, sham surgery trials in PD are a highly specialised type of research and any generalisations must be made with caution. Finally, in combining subject data from three different clinical trials, we interviewed subjects (due to sponsor requests) at various time points from the initial point of informed consent for their trials, with long lags in some cases.

In conclusion, we found that therapeutic motivation for entering sham surgery trials is very common, and having one's own doctor as the researcher is common. These factors did not specially increase the TM-related phenomena, and overall understanding of the purpose of research and of the research procedures was high. Although most subjects gave overly optimistic responses about potential benefits, their explanations present a complicated picture, as has been shown in other studies.5 ,17 We also saw an alternative role that therapeutic motivation may play: rather than leading people to false understandings and inaccurate assessment of risks and benefits, therapeutic motivation may indicate a ‘self-interested’ decision maker who is more rather than less likely to pay attention to factors pertaining to their welfare and rights. Finally, our results show that eliciting subjects’ understanding of purpose of research is more complicated than is commonly assumed, by methods that use one or two closed-ended questions to assess it. In future research, such assessments may need specific validation to ensure that intended phenomena are being measured.

Acknowledgments

The authors wish to thank the subjects who so generously gave their time and shared their experiences with them. They also wish to thank Ceregene, Inc. and Raymond T Bartus, Ph.D., Executive Vice President and Chief Scientific Officer, for thoughtful comments on the study and access to the patients who were involved in their CERE-120 Phase 2 clinical study; Christine V Sapan and Neurologix, Inc in providing access to the patients involved in their GAD 2 clinical trial; and Titan Pharmaceuticals, Inc for their cooperation.

References

Footnotes

  • Contributors SYHK: Will serve as guarantor. Substantial contributions to the conception and design of the work and the analysis and interpretation of data for the work; drafting and revising it critically for important intellectual content; final approval of the version to be published; agrees to be accountable for all aspects of the work. RDV and SP: Substantial contributions to analysis and interpretation of data for the work; drafting and revising it critically for important intellectual content; final approval of the version to be published; agrees to be accountable for all aspects of the work. RW and HMK: Substantial contributions to analysis and interpretation of data for the work; revising it critically for important intellectual content; final approval of the version to be published; agrees to be accountable for all aspects of the work. SF, RGH and KK: Substantial contributions conception and design of the work; revising it critically for important intellectual content; final approval of the version to be published; agrees to be accountable for all aspects of the work.

  • Funding This work was supported by the National Institute for Neurological Disorders and Stroke (R01-NS062770) and a CTSA award (UL1 RR024160) from the National Center for Research Resources and the National Center for Advancing Translational Sciences of the National Institutes of Health.

  • Disclaimer The views expressed are the authors’; they do not represent any position or policy of the National Institutes of Health, the Department of Health and Human Services, or the US government.

  • Competing interests None.

  • Ethics approval The Institutional Review Boards of the University of Rochester and the University of Michigan reviewed the study and deemed this study exempt from US federal regulations.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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