Background: Informed consent in clinical research is mandated throughout the world. Both patient subjects and investigators are required to understand and accept the distinction between research and treatment.
Aim: To document the extent and to identify factors associated with therapeutic misconception in a population of patient subjects or parent proxies recruited from a variety of multicentre trials (parent studies).
Patients and methods: The study comprised two phases: the development of a questionnaire to assess the quality of informed consent and a survey of patient subjects based on this questionnaire.
Results: A total of 303 patient subjects or parent proxies were contacted and 279 questionnaires were analysed. The median age was 49.5 years, sex ratio was 1 and 61% of respondents were professionally active. Overall memorisation of the oral or written communication of informed consent was good (69–97%), and satisfaction with the process was around 70%. Therapeutic misconception was present in 70% of respondents, who expected to receive better care and ignored the consequence of randomisation and treatment comparisons. This was positively associated with the acuteness and severity of the disease.
Conclusion: The authors suggest that the risk of therapeutic misconception be specifically addressed in consent forms as an educational tool for both patients and investigators.
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Informed consent for patient subjects in clinical research was gradually implemented following the Declaration of Helsinki (1964–2004) and is, to date, the one form of patient information that is standardised throughout the world. Meanwhile, consent to medical procedures other than those related to research is provided in most countries though a variety of routes, most often supported with written documents and sometimes confirmed by patient signature.1–3 In France, the “Huriet law”, passed in 1988, made it obligatory for clinical trial investigators to inform patients of the purpose, risks and benefits of the proposed research and to obtain signed consent. The information given to the patient concerns both the trial and the general rules that apply to clinical research; for example, that patients may at any time withdraw from the trial.4
Revisions to the Declaration of Helsinki give a good indication of how progressive the acceptance was, by physician-researchers, of biomedical research as a situation distinctly different from routine care.5 6 The original Declaration of Helsinki (1964), in line with the Nuremberg Code,7 aimed to protect subjects from potential totalitarian abuses of medical research. The first revision (Tokyo, 1975) imposed the review of research projects by an independent committee, while the last major revision (Edinburgh, 2000) focused on the risk that subjects could mistake research process for routine care when research is combined with care, typically in teaching hospitals.5–7 The hospital was thus identified with a favourable environment for misunderstanding and therapeutic misconception on the part of patient subjects. We use here the definition of therapeutic misconception proposed by Sugarman et al8
the inaccurate belief on the part of participants in research that research procedures involve individualised treatments selected primarily for the benefit of the participants.
Previous studies have analysed the process and outcome of communicating information in a trial and have made recommendations for physicians or other health professionals.9–12 These analyses resulted in the design of disease (or population) specific instruments13 14 for informed consent and provided knowledge on interventions that may improve the understanding of information by patient subjects.15 Endpoints to assess the quality of information provided include patient’s satisfaction, knowledge, understanding, recall and absence of therapeutic misconception. Because of the current emphasis on informed consent in both routine care and research involving routine elements of care, therapeutic misconception was our primary focus. Other authors have investigated therapeutic misconception in the setting of intensive care units and cancer patients in particular.16–18 and shown how difficult it was to make sense of treatment decisions in a research context. The difficulties and confusion resulted in particular from the belief that treatment was based on individual needs or that randomisation was not really carried out.19
We had the opportunity to use the setting a large consortium of university hospital to undertake a study on several trials addressing diverse medical situations and concerning different interventions.
Our objective was to document the extent and to identify predictors of therapeutic misconception in a population of patient subjects recruited from a variety of multicentre trials (parent studies), with the ultimate goal of helping investigators and patients distinguish research from usual care.
PATIENTS AND METHODS
The study comprised two phases: the development of a questionnaire to assess the quality of informed consent and a survey of patient subjects based on this questionnaire. A third phase which comprised an in-depth analysis of the quantitative results of the questionnaire was subsequently organised. Its results will be reported in a separate publication.
Phase 1: development of the questionnaire
In the first phase of the study, a questionnaire to assess patients’ understanding, recollection and misconception was developed based on a review of the relevant literature from 1988 to 2002 and on the results of a qualitative survey conducted between 1997 and 2001. Details of this preliminary fieldwork have been published.20 Domains selected from the first phase were translated into questions exploring knowledge, recall, understanding, motivation and satisfaction, location of the interview, and presence of a third party.
The questionnaire comprised four sets of questions (see appendix 1 online). The first set covered demographic data (sex, age, family status, diagnosis); the second set provided the normative information on the parent study that was necessary to check the appropriateness of subsequent answers (type of study—diagnostic or therapeutic—type of sponsor, main study setting—hospital or patient’s house—and study examinations and procedures). The third set, which comprised the bulk of the questionnaire, contained preliminary questions on patient knowledge and recall of the informed consent to assess whether patient subjects had the relevant background information that would enable us to pursue our analysis of therapeutic misconception (filter questions). The subsequent questions were more directly aimed at therapeutic misconception, with an assessment of patients’ understanding of the research situation and of their motivation to participate in the trial. For trials involving children, a specific questionnaire was designed for the proxy parent. The fourth part was tailored to the type of study concerned. Overall satisfaction with the communication and process of informed consent was finally checked. The interviewers recorded patients’ answers and verbatim comments. The items defining therapeutic misconception were adapted from Sugarman et al.21 A preliminary version of the questionnaire was tested on six patients and changes were made to improve clarity and include items that frequently recurred in the verbatim.
Phase 2: patient recruitment and data collection
Five participating institutions agreed that our research team would be informed of all diagnostic and therapeutic clinical trials that started recruiting patients in 2003. Healthy volunteers and patients with mental disorders were excluded. A member of the research team (PA) requested prior agreement from both the principal investigator of the parent study and the patients. The list of patients enrolled in the parent trials was obtained from the trial managers to avoid selection by the trial investigators. Of the 59 eligible trials, 35 provided our population of patient subjects. The other 24 trials were not included because of refusal from the principal investigator (often justified by quality-of-life outcome measurements that could be biased by our study) or no opportunity to interview the patients. Ten consecutive patients were eligible from each trial.
The study sites were all in- or outpatient departments in the participating hospitals that had ongoing trials. The face-to-face interview using the questionnaire developed in phase 1 took place during hospitalisation or clinic visit.
The protocol was approved by the ethics committee of Henri Mondor hospital (the coordinating centre). Patients were informed that this research was being done in collaboration with their physician, that they might decline the interview, and that their answers remained confidential and anonymous.
To estimate the number of patient subjects required, we considered that 80% of the population of patient subjects could misunderstand the consent. To estimate the 80% rate with a precision of 5% and a bilateral risk of error α 5%, a total of 250 patients were needed. Assuming 20% incomplete questionnaires due to early discharge from the hospital or clinic, missing information on the parent trial, or other difficulties, we aimed at recruiting 300 patient subjects.
Qualitative variables were described as counts (percentages) and quantitative variables as medians (quartiles). Comparisons were based on the χ2 test. All tests were two-tailed and analyses were performed using SAS V.9.12 (SAS Inc, Cary, North Carolina, USA).
We identified 350 eligible patients of which 47 had already left the hospital. A total of 303 patient subjects or parent proxies were contacted; 14 refused the interview. Of the remaining 289, five were not aware that they had participated in the parent trial and could not answer. For another five patient subjects, questionnaire information was incomplete (fig 1). A total of 279 questionnaires from respondents were analysed: 187 were direct interviews of patient subjects and 91 of proxy parents (mother 67, father 18, both 6).
Full results of the questionnaire are presented in the appendix online.
The median age was 49.5 (39–58) years for patient subjects and 40 (35–45) years for proxy parents. The sex ratio was 1; 61% of respondents were professionally active. Most patient subjects (85%) lived in households of 2–7 persons, while 15% (N = 43) lived alone. For paediatric studies (N = 91), all but one child lived with the parent respondent. Of the sample, 16% (N = 46) had finished education at primary level, 39% (N = 110) at secondary level, and 44% (N = 123) had obtained college or university degrees. Most respondents (N = 232; 83%) were native French speakers and the remaining 47 (17%) had good mastery of the language according to the interviewers. Overall, 162 patients were participating in a therapeutic trial and 117 in a diagnostic trial. Ninety-four patients suffered from an acute and 185 from a chronic condition; the prognosis was vital in 124 (McCabe 1 or rapidly fatal disease with a 6 month life expectancy on average) and functional in 155 cases (McCabe 2 or 3, or life expectancy from 5 years to normal).
The informed consent form was signed either immediately or on the same day as the proposal to participate by 119 patients (43%) and later by 144 patients (52%); 138 patients were alone with the investigator at the time, while 120 were with a third party who was equally likely to be a member of the family or part of the medical team.
Knowledge and recall
The word most frequently used to describe the parent study was research (N = 104) but protocol (N = 89), study (N = 63), trial (N = 21), “experiment” (N = 9) were also used. Nearly all patients (N = 269; 96%) remembered giving written informed consent, 261 (94%) recalled the type of study in which they were participating (therapeutic or diagnostic). Overall memorisation of the oral or written communication of informed consent was good: 265 patients (95%) remembered that they could refuse to participate, 212 (79%) knew that they had a copy of a signed consent form, 203 (73%) remembered the objectives of the study, 214 (77%) knew the duration of the study and 192 (69%) were aware of respect of patient’s privacy.
When patient subjects were asked more precise questions about the content of the informed consent, recall was fair: 228 (82%) remembered that they could withdraw from the trial at any time, 76 (27%) about the law protecting patient subjects, 57 (20%) about ethics committee approval and 49 (17%) about insurance.
Knowledge and recall for therapeutic studies (N = 117) increased with the level of education (p<0.001), in particular regarding the possibility of withdrawing from the trial, for which 85% of respondents (N = 39) with primary education gave a wrong answer versus 52% (N = 57) and 44% (N = 54) of respondents with secondary or university education, respectively.
Most patients (N = 204; 73%) were satisfied with the information they received, 79% (N = 221) considered that they had been sufficiently informed; 82% (N = 228) believed that it would be easy to obtain additional information if they wished, although only 25% (N = 70) stated that they had received additional useful information, which came mostly through the physician investigator.
Misconception (for both diagnostic and therapeutic interventions)
Elements of patients’ motivation to participate in a study and misconception are presented in table 1; 54% (N = 152) considered that being enrolled in a research protocol, whether diagnostic or therapeutic, increased their chances of cure and 52% (N = 145) that risks were not increased compared to usual care. The belief that participation in a trial permitted “to benefit from the best treatment” was found in 193 (69%) respondents. Technical aspects of the difference between research and usual care were correctly understood by 63% of respondents with regard to placebo (N = 175) and only 15% (N = 41) for randomisation. Among patients who participated in a therapeutic study (N = 162), 147 (90%) could properly label it as therapeutic, 20 (12%) answered correctly that their treatment was randomised, while 31 (19%) thought it had been chosen by their physician, the manufacturer or the scientific committee, and 96 (59%) did not know the answer. Participants in diagnostic studies (N = 117) overwhelmingly ignored the comparison (N = 78; 67%) or did not know; among the 18 patients who correctly described a comparison, only two knew about the randomisation. One-third of the population did not acknowledge the research situation, either not considering their contribution of their participation to the advancement of research (N = 30; 11%) or to the benefit to others (N = 57; 20%).
Despite these elements of misconception, 89% (N = 249) of respondents answered that the parent study aimed “to improve knowledge on mechanisms or treatments of disease” and 80% (N = 222) “to help others”, indicating beneficence as an important reason for participating in a study (verbatim).
A total of 233 (83%) patients manifested therapeutic misconception, either expecting the best treatment or a better chance of cure at no increased risk.
The factors associated with therapeutic misconception are presented in table 2 (patients who expect to benefit from the best treatment) and table 3 (patients who expect either the best treatment, increased chance of cure, or no increased risk). Severity and poor vital prognosis of the disease appeared to be strongly associated with therapeutic misconception; delay from consent to signature was also predictive but to a lesser extent.
We have assessed the recall and understanding of trial information of 279 patient-subjects or proxy parents participating in clinical research on diagnostic or therapeutic interventions. Patients have a fair recall of important technical elements of their consent such as the possibility to refuse or withdraw from the trial, the objectives and duration of the study, the protection of their privacy. Not surprisingly this recall increased with educational level. We also confirmed that therapeutic misconception, or the identification of a research situation implies the ability to understand that the process of care was designed for an experiment and not to benefit patients’ individual health was an important element of patients’ participation. Therapeutic misconception was present in over two-thirds of respondents, who expected an individual benefit from participating in a clinical research study. Patients views on their participation was a mixture of self interest and misconception with altruism and faith in medical progress through research. Misconception was more likely to occur in patients suffering from an acute life-threatening condition and was not affected by the educational level. This finding confirms the findings of Snowdon et al16 on parents from critically ill babies. Therapeutic misconception might be due to the difficulty to accept medical uncertainty for a very severe condition or to the ambiguous presentation of information. Patients could believe that these general statements are addressed to them personally.17 Information documents distributed to patients in French hospital could be misleading: they contain such statements as “if you are offered participation in a clinical trial, it is to improve the treatment of your child’s illness”,22 whereas for adults the information reads “if you are offered participation in a trial it is to improve the treatment of your illness in the future”.23
The focus groups confirmed that obtaining personal benefit was considered a just reward for the additional requirements of a research protocol.
Other authors24–26 have identified the need for means to help patients understand the research perspective. The focus seems to have shifted from the understanding and recall of elements of information15 to the identification of a whole situation distinct from usual care8 20 27 and therefore to finding means to reduce therapeutic misconception.28 It may be, however, that both investigators and patient subjects have converging interests to maintain the pretence at the heart of therapeutic misconception. Investigators are reluctant to discuss the elements that clearly separate research from usual care—randomisation, equipoise, uncertainty28 29—and patients prefer to believe that treatment decisions are specific to their own case,24 30 and also may dislike the idea of randomisation and uncertainty about the treatment given.27 Given these concerns, careful avoidance of clarification appears a pragmatic, albeit unethical, option.
Our study has limitations. The overall process of interviews, focus groups, and data analysis extended over six years; however, the same investigators remained in charge of the study, ensuring consistency of purpose and methods. French law changed in 2004 to follow the 2000 revision of the Helsinki declaration. The distinction between therapeutic and non-therapeutic research was abandoned but the focus is now on differentiating research from usual care. International comparisons may be hazardous given the different attitudes of the population towards medical research, different financial incentives, and different litigation processes. While researchers in the field of patient information have uniformly outlined the need to address therapeutic misconception, it remains to be tested whether solutions developed in one setting apply to another. We suggest that country-specific focus groups might help phrase straightforward explanations that enable patient subjects to differentiate a research situation from usual care.
The next step proposed is the development of instruments that can be used ex ante to design better information tools or ex post to test the quality of informed consent from trial participants.8 31 Other complementary approaches include patient support such as ability to talk with patients with the same experience of decision-making.24 We suggest that investigators should also be targeted for education: they bear the responsibility of the explanation to patients, and should therefore be convinced of the importance of countering therapeutic misconception. The material currently circulated to inform patients could be critically appraised to train the communication skills of investigators and in particular to differentiate benefit for the treatment of the disease from benefit for the treatment of the patient-subject. Ethics committees could have a leading role in the process as they are in contact with investigators and have important leverage. Educational material should be circulated both at the time of protocol design via the administrations in charge of calls for proposals and at the time of protocol submission by the Ethics committees.
As the enrollment of patients in clinical trials is becoming increasingly difficult24 and expensive for populations with generalised social health insurance, it will be interesting to follow the implementation of these instruments to assess their acceptance by investigators. This might differ between countries where medicine has retained a strong paternalistic component and those where the emphasis is on patient autonomy.32 In the former, investigators may view these instruments as yet another obstacle, whereas in the latter they might improve communication between ethics committees and the research community.
The authors are indebted to I Evrard and M Mallet, who were in charge of patient interviews. S Rushton-Smith provided editorial assistance and was funded by Association Naturalia et Biologia.
Competing interests: None declared.
Funding: This project was financed in part by a grant from the French Ministry of Health PHRC AOM98123.
Ethics approval: The study was approved by the ethics committee of Henri Mondor hospital, Créteil, France.
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