Participants’ understanding of informed consent in clinical trials over three decades: systematic review and meta-analysis

Abstract Objective To estimate the proportion of participants in clinical trials who understand different components of informed consent. Methods Relevant studies were identified by a systematic review of PubMed, Scopus and Google Scholar and by manually reviewing reference lists for publications up to October 2013. A meta-analysis of study results was performed using a random-effects model to take account of heterogeneity. Findings The analysis included 103 studies evaluating 135 cohorts of participants. The pooled proportion of participants who understood components of informed consent was 75.8% for freedom to withdraw at any time, 74.7% for the nature of study, 74.7% for the voluntary nature of participation, 74.0% for potential benefits, 69.6% for the study’s purpose, 67.0% for potential risks and side-effects, 66.2% for confidentiality, 64.1% for the availability of alternative treatment if withdrawn, 62.9% for knowing that treatments were being compared, 53.3% for placebo and 52.1% for randomization. Most participants, 62.4%, had no therapeutic misconceptions and 54.9% could name at least one risk. Subgroup and meta-regression analyses identified covariates, such as age, educational level, critical illness, the study phase and location, that significantly affected understanding and indicated that the proportion of participants who understood informed consent had not increased over 30 years. Conclusion The proportion of participants in clinical trials who understood different components of informed consent varied from 52.1% to 75.8%. Investigators could do more to help participants achieve a complete understanding.


Introduction
Informed consent has its roots in the 1947 Nuremberg Code and the 1964 Declaration of Helsinki and is now a guiding principle for conduct in medical research. 1,2 Within its ethical and legal foundations, 3 informed consent has two specific goals in clinical research: (i) to respect and promote a participant's autonomy; and (ii) to protect participants from harm. 4,5 Obtaining written informed consent from participants before enrolment in a study is an internationally accepted standard. [6][7][8][9][10] Five concepts must be considered in establishing informed consent: voluntariness, capacity, disclosure, understanding and decision. 11,12 Voluntariness means that an individual's decision to participate is made without coercion or persuasion. Capacity relates to an individual's ability to make decisions that stems from his or her ability to understand the information provided. Disclosure involves giving research participants all relevant information about the research, including its nature, purpose, risks and potential benefits as well as the alternatives available. 13 Understanding implies that research participants are able to comprehend the information provided and appreciate its relevance to their personal situations. Decision is that made to participate, or not. 11,12 The quality of informed consent in clinical research is determined by the extent to which participants understand the process of informed consent. 14 Understanding plays a pivotal role in clinical research because it directly affects how ethical principles are applied in practice. [15][16][17] Although the literature on informed consent began to accumulate in the 1980s, little is known about how patients' understanding has evolved as no meta-analysis has been previously performed. A systematic review considering literature up to 2006 found that only around 50% of participants understood all components of informed consent in surgical and clinical trials. 18 Another systemic review, which included data up to 2010, compared only the quality of informed consent in developing and developed countries. 19 The objective of this study was, therefore, to investigate the quality of informed consent in clinical trials in recent decades by performing a systematic review and metaanalysis of the data available.

Systematic reviews
Trial participants' understanding of informed consent Nguyen Thanh Tam et al.
October 2013. In addition, we analysed the reference lists of relevant articles. All studies identified were reviewed independently for eligibility by two of five authors and conflicts were resolved by seeking a consensus with other authors.
A study was eligible for inclusion if it assessed the participant's or the participant's guardian's understanding of informed consent 1,2 and at least one of the following components of the informed consent process: 8,21 therapeutic misconception (i.e. lack of awareness of the uncertainty of success); ability to name at least one risk; knowing that treatments were being compared; or understanding of: (i) the nature of the study (i.e. awareness of participating in research); (ii) the purpose of the study; (iii) the risks and side-effects; (iv) the direct benefits; (v) placebo; (vi) randomization; (vii) the voluntary nature of participation; (viii) freedom to withdraw from the study at any time; (ix) the availability of alternative treatment if withdrawn from a trial; or (x) confidentiality (i.e. personal information will not be revealed). There was no restriction by language, age (i.e. children or adults) or study design. French and Japanese articles were translated into English by authors with a good command of these languages. We excluded articles on studies that: (i) compared or evaluated methods of informed consent; (ii) used an intervention to improve participants' knowledge of informed consent; (iii) involved animals or included only healthy volunteers (e.g. simulated studies); (iv) involved patients with cognitive deficits; (v) were published as posters, in conference proceedings or as a thesis; or (vi) were not clinical trials. Our study protocol was registered with the international prospective register of systematic reviews (PROSPERO) with the identifier CRD42013005526. The study selection process, which was carried out in accordance with MOOSE guidelines for meta-analyses and systematic reviews of observational studies, is shown in Fig. 1. 22

Quality of evaluation
The quality of the informed consent evaluation was assessed independently by two authors using seven metrics: (i) the description of participants; (ii) whether or not interviewers were members of the original trial's staff; (iii) the description of the evaluation method (i.e. by questionnaire or interview); (iv) the description of the questionnaire; (v) the selection of participants (i.e. consecutive participants or a random or cross-sectional selection); (vi) the description of exclusion criteria; and (vii) the timing of the evaluations. Quality scores for the studies included are shown in Appendix A (available at: https://www.researchgate.net/publication/270506278_Online_Only_Supple-ments_for_Three_decades_of_par-ticipants_understanding_of_informed_ consent_in_clinical_trials_a_system-atic_review_and_meta-analysis).

Study data
Data were extracted for each study on: (i) the year of publication; (ii) the study language and the country where the study was conducted; (iii) the phase of the study; (iv) the baseline characteristics of the study population, including the source of the population, the number of participants and their age, sex and educational level; (v) the medical specialty of the clinical research, including the seriousness of the disease studied; (vi) the method and timing of the informed consent evaluation; (vii) the type of questions participants had to answer; and (viii) the components of informed consent assessed, including understanding of the nature and purpose of the study, knowing that treatments were being compared, therapeutic misconceptions, participants' ability to name risks, awareness of potential risks and side-effects and understanding of potential benefits, randomization, placebo, the voluntary nature of participation, freedom to withdraw at any time, confidentiality and the availability of alternative treatment.

Statistical analysis and data synthesis
If a study investigated more than one population, a data set was created for each population. The proportion of participants who understood the different components of informed consent was pooled across studies using Comprehensive Meta-Analysis software version 2.0 (Biostat, Englewood, United States of America) and was expressed as a percentage with 95% confidence intervals (CIs). The heterogeneity of study findings was evaluated using the Q statistic and the I 2 test and was considered significant if the P-value was < 0.10. Since studies gave heterogeneous results for all components, the proportion of participants who understood each component was pooled using a random-effects model that included weighting for each study. In examining the effect of covariates on these proportions, we used a subgroup or meta-regression analysis when eight or more studies assessed a particular covariate. Differences between subgroups and trends were considered significant if the P-value of Cochran's Q test was < 0.05. 23 To determine if publication bias was present, we used Begg's funnel plot and Egger's regression test: a P-value < 0.10 indicated significant publication  bias. 24 When publication bias was present, we used Duvall and Tweedie's trimand-fill method to enhance symmetry by adjusting for studies that appeared to be missing. [25][26][27] The final proportion of participants who understood each component was computed after adjustment for missing studies.

Results
The final analysis included 103 studies: 85 from the database search and 18 from reviewing reference lists.  Ultimately 135 data sets were included because some studies evaluated more than one population (Appendix A). The sample size ranged from 8 to 1789 participants and the response rate to interview questions ranged from 9.3% to 100%. Participants were adults in 95 data sets, parents or guardians in 34, adult and child patients in three, child patients in two and adult patients or parents in one. Overall, 79% (106) of data sets were conducted in middle-or high-income countriesas classified by the World Bank 131 -and 67% (90) did not report the phase of the clinical trial. The medical specialty was cancer in 33% (44) of data sets, infectious disease in 14% (19), vaccines in 10%, (13) cardiovascular disease in 7% (9), neurology in 6% (8) and other in 31% (42). Moreover, 98% (132) were published in English and only 1% each in Japanese (1) and French (2). Details of the studies and data sets are presented in Table 1 (available at: http://www.who. int/bulletin/volumes/93/3/14-141390).

Effect of covariates
We performed a meta-regression analysis to evaluate the influence of particular covariates on the proportion of participants who understood informed consent ( Table 2). We found that gender had no effect but that, importantly, significantly fewer patients from low-income countries than from middle-and high countries understood randomization, the voluntary nature of participation and freedom to withdraw at any time. In addition, critically ill patients were significantly less likely to understand the nature or benefits of the study or confidentiality or to be able to name at least one risk. However, older participants were more likely to understand the nature of the study and freedom to withdraw at any time. A lower educational level was associated with a reduced likelihood of understanding the nature of the study, placebo, randomization and freedom Trial participants' understanding of informed consent Nguyen Thanh Tam et al.
to withdraw at any time. Participants in phase-I clinical trials were less likely than participants in phase-II, -III or -IV trials to understand the purpose of the study and were more likely to have therapeutic misconceptions. Participants in phase-I trials were also more likely to understand potential risks and side-effects and freedom to withdraw at any time. Participants assessed using open-ended questions were less likely to understand the purpose of the study (Fig. 3), the voluntary nature of participation or freedom to withdraw at any time or to be able to name at least one risk. Additionally, the later the evaluation of understanding was carried out, the less likely the participant was to understand confidentiality or to be able to name at least one risk. The quality of the evaluation did not influence understanding.
Our data also provided us with the opportunity to analyse how study participants' understanding of informed consent had changed over 30 years. Surprisingly, there was no significant change in understanding of any component (Fig. 4, Fig. 5 and Fig. 6). In particular, we were interested in the past 20 years, after the World Health Organization introduced guidelines for good clinical practice in trials. 132 After removing four early studies, we again found no significant change in understanding of any component, including the freedom to withdraw (Fig. 7). Furthermore, there was no significant change in understanding of any component over the past 13 years in all studies combined or in subgroups of participants, including those assessed using open-ended questions, those assessed using closed-ended questions and those in middle-and high-income countries assessed using closed-ended questions (Appendices C, D, E and F, respectively available at: https://www.researchgate.net/publication/270506278_Online_Only_Supple-ments_for_Three_decades_of_par-ticipants_understanding_of_informed_ consent_in_clinical_trials_a_system-atic_review_and_meta-analysis).

Discussion
Obtaining informed consent from participants in clinical research is essential because it promotes their welfare and ensures their rights. 9,133 However, participants must have a good understanding of what informed consent entails. Our meta-analysis indicates that around 75% of individuals understood the nature of the study, their right to refuse to participate, their right to withdraw at any time and the direct benefits of participation. This percentage is higher than the figure of around 50% found in a previous systematic review 18 probably because we included only clinical trials, excluded studies of patients with cognitive deficits and weighted the meta-analysis to account for heterogeneous data.
Our data also highlight the difficulty participants had in understanding particular components of informed consent, such as randomization and the use of placebo. Moreover, although

Systematic reviews
Trial participants' understanding of informed consent Nguyen Thanh Tam et al.
participants were aware of potential risks and side-effects, they were less likely to be able to name at least one risk and, although they understood the benefits of participating in a study, they were less aware of the uncertainty of these benefits (i.e. had therapeutic misconceptions). These findings were also noted in previous studies. 18,19,[134][135][136][137] They are, perhaps, not surprising since a participant's understanding depends, to a certain degree, on their literacy as well as on the duration of the informed consent process and the explanatory skills of the researchers. [138][139][140] In addition, the meta-regression was able to identify differences in understanding of informed consent between population groups. Older participants more often than younger participants understood the nature of the study and freedom to withdraw at any time. The reason for this difference requires further study. As noted in a previous systematic review, 19 participants from developing countries were less likely than others to understand the voluntary nature of participation and freedom to withdraw at any time. It is possible that patients in these countries dare not refuse to join or dare not withdraw from a study because they fear their doctor's disapproval. 141 Participants from developing countries and those with a low level of literacy were less likely to understand randomization.
Phase-I clinical trials are usually conducted in small numbers of participants to test a drug's safety and dose range. Consequently, it was expected that participants in phase-I trials would be less likely than those in more advanced trials to understand the purpose of the study or that the benefits were uncertain. In contrast, participants in phase-I trials were more likely to be aware of potential risks and of their freedom to withdraw at any time.
Compared with the use of openended questions to evaluate participants' understanding, the use of closed-ended questions was associated with higher rates of understanding of the purpose of the study, the voluntary nature of participation and freedom to withdraw and with a greater likelihood of being able to name at least one risk. However, the use of closed-ended questions could have led to understanding being overestimated because respondents had to choose from a limited number of possible answers and did not have to think clearly about the issues. 142 Consequently, the use of open-ended questions may have reflected better the true extent of understanding since respondents had to put their understanding into words. 143 Finally, an unexpected finding of our analysis was that understanding of the potential risks and side-effects of trials, of placebo and of freedom to withdraw had not changed over 30 years. This is despite considerable progress in medical research methods over this time 144 and many attempts made to improve the quality of informed consent. 145 There are four possible explanations: (i) the maximum proportion of participants who understand these concepts has been reached; (ii) the increasing complexity of clinical trials has made the informed consent process longer and more difficult to understand; (iii) not enough effort has been put into enhancing the quality of the informed consent process; and (iv) our analysis did not have the statistical power to detect a significant increase in understanding. In fact, the best way to improve understanding of informed consent is still debated. A recent meta-analysis of interventions for improving understanding found that enhanced consent  Trial participants' understanding of informed consent Nguyen Thanh Tam et al.
forms and extended discussions led to significant increases in understanding whereas multimedia approaches did not. 146 In other words, simple measures such as well formatted, easily readable consent forms and intensive discussions with participants may be more effective than more complex measures. 140,[146][147][148] Although an understanding of all the components of informed consent we investigated is required for patients to make a decision on study participation, some components were assessed more often than others. We found a good correlation between the likelihood that a participant would understand a specific component of informed consent and the number of studies that investigated understanding of that component (Appendix G). This suggests either that it was simpler to evaluate understanding of some components or that some components were more important.
One limitation of our study is that we were not able to analyse the effect on understanding of informed consent of the presence of a nurse during the informed consent process, of the duration of the process or of participants choosing not to take part in a clinical trial because only a small number of studies investigated these factors. Moreover, only 79 of the 135 data sets gave information on whether the interviewers were investigators in the original clinical trial. Hence, we were not able to analyse the effect of this factor on the results. Another limitation is that we included studies of children because they have the right to decide whether to participate. 149,150 However, the number of studies involving children was small and our sensitivity analysis showed that removing these studies did not influence the pooled results. Although we found a high level of heterogeneity across studies for understanding of all components of informed consent and although Cox et al. suggest that, in these circumstances, individual studies should be described rather than combined in a meta-analysis, 151 we, like other groups, chose to perform a meta-analysis with a regression analysis and subgroup analysis to gain a better insight into how covariates affect understanding. [152][153][154] In conclusion, we found that most participants in clinical trials understood fundamental components of informed consent such as the nature and benefits of the study, freedom to withdraw at any time and the voluntary nature of participation. Understanding of other components, such as randomization and placebo, was less satisfactory and has not improved over 30 years. Our findings suggest that investigators could make a greater effort to help research participants achieve a complete understanding of informed consent. This would ensure that participants' decision-making is meaningful and that their interests are protected. ■ Competing interests: None declared. a The logit event rate is the natural logarithm of the event rate divided by (1 -event rate), where the event rate is the proportion of study participants who understood they were free to withdraw from the study at any time.

Fig. 7. Participants' understanding of their freedom to withdraw from a study at any time, after introduction of WHO guidelines for good clinical practice in trials 132
Logit event rate a 6.00 a The logit event rate is the natural logarithm of the event rate divided by (1 -event rate), where the event rate is the proportion of study participants who understood they were free to withdraw from the study at any time.

La comprensión del consentimiento informado por parte de los participantes de ensayos clínicos a lo largo de tres décadas: revisión sistemática y metaanálisis
Objetivo Estimar la proporción de participantes de ensayos clínicos que comprende los distintos componentes del consentimiento informado. Métodos Se identificaron los estudios pertinentes mediante una revisión sistemática de PubMed, Scopus y Google Scholar y el examen manual de listas de referencia a fin de hallar publicaciones anteriores a octubre de 2013. Se realizó un metanálisis de los resultados del estudio mediante un modelo de efectos aleatorios para tener en cuenta la heterogeneidad.