Participants’ understanding of informed consent in clinical trials: A systematic review and updated meta-analysis

Roles Conceptualization, Data curation, Formal analysis, Writing – original draft Affiliation Department of Molecular Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China ⨯

Roles Methodology, Writing – original draft Affiliation Department of Molecular Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China ⨯

Roles Resources, Writing – review & editing Affiliation Department of Molecular Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China ⨯

Roles Formal analysis Affiliation Department of Molecular Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China ⨯

Roles Data curation Affiliation Department of Molecular Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China ⨯

Roles Data curation Affiliation Department of Molecular Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China ⨯

Roles Formal analysis Affiliation Department of Molecular Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China ⨯

Roles Validation, Writing – review & editing * E-mail: jiangxieyuan@126.com Affiliation Beijing Jishuitan Hospital, Capital Medical University, Beijing Research Institute of Traumatology and Orthopaedics, Beijing, China

Participants’ understanding of informed consent in clinical trials: A systematic review and updated meta-analysis

Figures

Abstract

Obtaining written informed consent from participants before enrolment in a study is essential. A previous study showed that only 50% of the participants in clinical trials understood the components of informed consent, and the methods of participants’ understanding of informed consent were controversial. This updated meta-analysis aimed to estimate the proportion of participants in clinical trials who understand the different informed consent components. PubMed, EMBASE, the Cochrane Library, and Scopus were searched till April 2023. Therapeutic misconception, ability to name one risk, knowing that treatments were being compared, and understanding the nature of the study, the purpose of the study, the risks and side-effects, the direct benefits, placebo, randomization, voluntariness, freedom to withdraw, the availability of alternative treatment if withdrawn from the trial, confidentiality, compensation, or comprehension were evaluated. This meta-analysis included 117 studies (155 datasets; 22,118 participants). The understanding of the risks and side-effects was investigated in the largest number of studies (n = 100), whereas comparehension was investigated in the smallest number (n = 11). The highest proportions were 97.5%(95% confidence interval (CI): 97.1–97.9) for confidentiality, 95.9% (95% confidence interval (CI): 95.4–96.4) for compensation, 91.4% (95% CI: 90.7–92.1) for the nature of study, 68.1% (95% CI: 51.6–84.6) for knowing that treatments were being compared, and 67.3% (95% CI: 56.6–78) for voluntary nature of participants. The smallest proportions were the concept of placebo (4.8%, 95%CI: 4.4–5.2) and randomization(39.4%, 95%CI: 38.3–40.4). Our findings suggested that most participants understood the fundamental components of informed consent (study confidentiality, nature, compensation, voluntariness, and freedom to withdraw). The understanding of other components, such as placebo and randomization was less satisfactory.

Citation: Wu C, Wang N, Wang Q, Wang C, Wei Z, Wu Z, et al. (2024) Participants’ understanding of informed consent in clinical trials: A systematic review and updated meta-analysis. PLoS ONE 19(1): e0295784. https://doi.org/10.1371/journal.pone.0295784

Editor: Maiken Pontoppidan, VIVE - The Danish Center for Social Science Research, DENMARK

Received: September 9, 2022; Accepted: November 29, 2023; Published: January 2, 2024

Copyright: © 2024 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All data generated or analyzed during this study are included in this published article.

Funding: The authors received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Unethical issues in human research led to the formal execution of the Nuremberg Code after the post-World War II Nuremberg Trials [1]. In 1978, the Belmont Report in the United States of America laid the basis for informed consent in research [2]. The Belmont Report introduced three basic ethical principles: 1) respect for persons, 2) beneficence, and 3) justice [2]. It also introduced the essentials for informed consent in research, including risk/benefit assessment and participant selection [3]. As detailed in the Belmont Report, informed consent has two specific goals in clinical research: 1) to respect and promote a participant’s autonomy and 2) to protect participants from harm [1, 2].

Obtaining written informed consent from participants before enrolment in a study is an internationally accepted standard [4, 5]. The investigators must take any means necessary to be sure that the participants understand that they have the right to decide whether they want to participate or not in a study voluntarily and that declining to participate will not affect the subsequent health care to which they are entitled to [4, 5]. The participant must be able to ask the investigators questions but must answer the investigators’ questions truthfully to ensure that their participation is safe. The investigators should ensure that the participants understand the potential benefits and risks of participating in the study and that they can freely stop participating without penalty [6].

Two major factors affect the quality of the informed consent: the investigator and the participant. On the investigator’s end, a wealth of regulatory mechanisms and principles (ethics committees, Good Clinical Practices, GCPs), sponsors, independent auditors, regulatory agencies, governments, etc.) are in place for the surveillance of the good conduct of a study [4, 5]. Furthermore, the quality of informed consent depends on participants’ understanding of the informed consent process. However, the participants’ literacy, the duration of the informed consent process, and the researchers’ skills in explaining the trial all affected the patient’s understanding of what informed consent was about [7–9]. This difference in understanding may lead to occurence in treatment misconceptions. Treatment misconceptions are often defined as "research participants not appreciating important differences between research and treatment." Treatment misconceptions can cause participants to deny the possibility of significant disadvantages or risks in participating in clinical trials, making it impossible for patients to objectively decide whether to participate in trials, and thus affecting the application of ethical principles in practice.

A systematic review of the literature published up to 2006 showed that only 50% of participants understood all components of informed consent in surgical and clinical trials [10]. Another systematic review, which included data published up to 2010, compared the quality of informed consent in developing and developed countries [11]. It was found that participants in developed and developing countries interpreted the study information differently, and both had a lower understanding of randomization and placebo-controlled designs than other aspects of the trial. Finally, in 2015, a meta-analysis investigated the quality of informed consent forms 103 clinical trials in recent decades and found that approximately 75% of clinical trial participants were aware of informed consent [12]. These studies found that the probability that patients were fully informed about informed consent increased over time. In addition, in order for patients to be fully informed about clinical trials, it is critical to identify areas where informed consent is weak. To better understand these conflicting data, we aimed to estimate the most recent evidence on the proportion of clinical trial participants who are aware of the different informed consent components. Our findings can guide improving the format and language of informed consent so that participants receive accurate, adequate and relevant information. Therefore, this study can identify the proportion of participants in clinical trials who understand the different informed consent components, and thus provide important reference value in improving the strategy of informed consent process.

Methods and measures

Literature search

This systematic review and meta-analysis (update) were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [13]. This review was not registered in the Cochrane Library or the prospective international register of systematic reviews (PROSPERO) registry platforms. PubMed, EMBASE, the Cochrane Library, and Scopus were systematically searched for studies published up to April 2023 using the MeSH terms "informed consent AND understanding AND (randomized controlled trials as topic OR clinical trial as topic)" and relevant keywords, followed by screening based on the eligibility criteria. The reference lists from the retrieved studies were also reviewed to identify any potentially eligible studies. The full search strategy and syntaxes were provided in S1 Table.

Eligibility criteria

The studies had to have assessed the participants’ or guardians’ understanding of informed consent to be included. They had to include at least one of the following components of the informed consent process: 1) therapeutic misconception (i.e., lack of awareness of the uncertainty of success); 2) ability to name at least one risk, 3) knowing that treatments were being compared; 4) understanding of i) the nature of the study (i.e., awareness of participating in the 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, x) confidentiality (i.e., personal information will not be revealed), xi) compensation, or xii) comprehension; 5) studies conducted by the same institution providing detailed information or newly published articles. There was no restriction for study design. Only articles in English or Chinese were included.

Articles under the following criteria were excluded: case reports, letters, reviews, comments, conference abstracts, studies conducted in animal models or in vitro experiments, studies in languages other than English or Chinese, and those not available were excluded.

Data extraction

Two independent reviewers performed the selection and inclusion of studies in two stages (N Wang and Q Wang). The selection process included the analysis of the titles/abstracts followed by the full texts. Disagreements were resolved by a third reviewer (C Wang). Data including names of the first author, publication year, study design, country, sample size, mean age, the seriousness of the disease studied, the phase of the study, the method and timing of the informed consent evaluation, the types of questions the participants had to answer; and the components of informed consent assessed were extracted.

Assessment of the quality of studies

About previous studies [12], the quality of the informed consent evaluation was assessed independently by two authors according to seven metrics: 1) the description of participants, 2) whether or not the interviewers were members of the original trial’s staff, 3) the description of the evaluation method (i.e., by questionnaire or interview), 4) the description of the questionnaire, 5) the selection of the participants (i.e., consecutive participants or a random or cross-sectional selection), 6) the description of the exclusion criteria, and 7) the timing of the evaluations. The score ranged from 0 to 7 points. A scale of 0 or 1 point indicated poor quality, 2–5 points as a medium, and 6–7 points as high quality.

Statistical analysis

The event rates and 95% confidence intervals (CIs) were used to determine the values of dichotomous data. Continuous data were evaluated using standardized mean differences (STDs) and the corresponding 95% CIs using the Mantel-Haenszel method [14]. All analyses were performed using STATA SE 14.0 (StataCorp, College Station, Texas, USA). In all cases, P-values

Results

Study selection

Fig 1 presents the study selection process. The initial search yielded 10246 records (including 27 that were identified by manual screening of reference lists). After removing the duplicates (n = 2050), 8186 records were screened, and 8041 were excluded. Then, 145 full-text articles were assessed for eligibility, and 28 were excluded because of no available data.

PowerPoint slide larger image original image Fig 1. Flowchart of study selection.

Characteristics of the studies

S1 Table presents the characteristics of the 114 included studies [7, 18–131] (155 datasets; 21,659 participants). The studies were published between 1980 and 2022, and the sample size ranged from 14 to 1786. The majority of the included participants were aged 30 years. Eleven studies were from East Asia, 43 were from Europe, 33 were from North America, six were from Oceania, five were from Latin America, 17 were from Africa, and one was international.

Quality assessment of studies

S2 Table presents the quality of the included studies. Five studies scored 2 points, 23 scored 3 points, 45 scored 4 points, 30 scored 5 points, and 11 scored 6 points (three studies had different parts that were evaluated separately). A total of 103 and 11 studies were deemed as medium and high quality, respectively.

Understanding of different components of informed consent

Fig 2 summarizes the results of understanding the different components of informed consent. The understanding of the risks and side-effects was investigated in the largest studies (n = 100), whereas comprehension was investigated in the smallest number (n = 11). The analyses showed variations in the proportion of participants who understood different components of informed consent. The highest proportions were 97.5% (95% confidence interval (CI): 97.1–97.9) for confidentiality, 95.9% (95% confidence interval (CI): 95.4–96.4) for compensation, 91.4% (95% CI: 90.7–92.1) for the nature of the study, 68.1% (95% CI: 51.6–84.6) for knowing that treatments were being compared, and 67.3% (95% CI: 56.6–78) for voluntary nature of participants. The smallest proportions were the concept of placebo (4.8%, 95%CI: 4.4–5.2) and randomization (39.4%, 95%CI: 38.3–40.4). There was some difference in the proportion of participants who understood the different components of informed consent, with the highest proportion being confidentiality and the lowest being the placebo concept.

PowerPoint slide larger image original image Fig 2. Components of informed consent.

Subgroup analyses

Subgroup analysis was performed at different trial stages (phase I study vs phase II-III studies), tumor or not (cancer vs non-cancer), informed consent recipients (participants themselves vs guardians or caretakers), critical condition (critical illness vs non-critical illness), and national development status (least developed countries vs developing countries vs developed countries). All 15 components of informed consent were included in the analysis, and the subgroup analysis results was presented in Table 1. Through subgroup analysis, it can be found that there are also certain differences in the proportion of participants who understand different components of informed consent among different subgroups.

PowerPoint slide larger image original image Table 1. Subgroup analyses.

Trial stages subgroup

Subgroup analysis results of the trial phase showed that a larger proportion of patients participating in the phase I trial had a better understanding of trial-related compensation (94.4% vs. 78.4%), no therapeutic misconception (63.5% vs. 58.1%), trial risks (62.7% vs. 49.8%), potential benefits of the trial (96.0% vs. 17.0%), randomization (89.4% vs. 28.0%), the right to withdraw (79.0% vs. 63.2%), and confidentiality (61.1% vs 47.7%).

Compared to patients participating in phase II-III, a similar proportion of phase I patients were able to understand that the study purpose and treatment were being compared.

However, a larger percentage of patients in phase II-III trials were able to name at least one risk (48.4% vs. 0%), understand the concept of placebo (8.6% vs. 0.7%), understand voluntary participation (68.6% vs. 58.9%), understand acceptable alternative therapies after discontinuation (52.7% vs. 39.5%) and comprehend the studies (63.3% vs. 25.3%).

Tumor patient subgroup

Compared with non-tumor patients, a larger proportion of tumor patients were able to have no misconceptions about the trial (57.9% vs. 42.8%), understand the potential benefits (59.8% vs. 49.5%), the right to withdraw (73.0% vs. 61.4%), and the availability of alternative treatments after withdraw (57.1% vs. 42.6%).

Cancer patients and non-cancer patients were equally likely to understand the compensation of the trial, voluntarily participate, the purpose of the trial, be able to name at least one risk, understand the risk, randomize, and confidentiality.

However, a smaller percentage of tumor patients were able to understand the placebo concept (7% vs. 0.5%), the treatment was compared (45.3% vs. 72.3%), and comprehend the studies (61.0% vs. 47.0%).

Informed consent recipients subgroup

Subgroup analysis showed that patients who signed informed consent themselves were better able to understand the risks of the trial (53.7% vs. 8.5%).

In understanding voluntary participation, the purpose of the trial, no therapeutic misconception, understand the treatment was being compared, the right to withdraw, the difference between patients signing informed consent and guardians or caregivers signing was not significant.

However, when guardians or caregivers signed informed consent, they tended to be better able to understand the compensation associated with the trial, name at least one risk (53.2% vs. 0.7%), understand the concept of placebo (24.4% vs. 6.3%), understand randomization (45.5% vs. 47.6%), understand the availability of alternative treatment after discontinuation (61.7% vs. 49.0%), and understand confidentiality (62.5% vs. 47.5%).

Critical condition subgroup

A larger proportion of critically ill patients were able to understand randomization (55.1% vs. 1.5%), availability of alternative treatment after discontinuation (68.3% vs. 48.8%), and confidentiality of the trial (47.7% vs. 61.1%).

Critically ill and non-critically ill patients had similar percentages in understanding voluntary participation, no therapeutic misconception, ability to name at least one risk, and understanding the right to withdraw.

Non-critically ill patients were better able to understand the trial-related compensation (94.6% vs. 95.9%), the purpose of the study (4.9% vs. 65.4%), the risks (54.0% vs. 36.9%), the potential benefits (56.0% vs. 3%), and the concept of placebo (24.4% vs. 6.3%).

National development status subgroup

According to the classification of the degree of development of countries by the United Nations, countries are divided into least developed countries, developing countries and developed countries according to their development conditions.

The results of the subgroup analysis showed that compared with developed and developing countries, a larger proportion of participants in the least developed countries were able to understand the purpose (78.4% vs 68.9% vs 68.3%), the potential benefits (88.8% vs 61.5% vs 55.5%), randomisation (65.7% vs 51.9% vs 55.5%), and the confidentiality of the trial (88.8% vs 63.1% vs 50.7%).

A greater proportion of participants in developing countries were able to understand trial compensation (67.1% vs 89.7% vs 61.8%), voluntary participation (71% vs 79.8% vs 73.4%), and no treatment misunderstandings (54.3 vs 85.2 vs 60.4). Be able to name at least one risk (57.7% vs 69.4% vs 59.3%), know the trial risk (56.4% vs 65.7% vs 49.3%), know that treatment is being compared (79.1% vs 60.9%), Understand the freedom to withdraw at any time (48.3% vs 72.3% vs 72%) and the availability of alternative therapies after withdrawal (49.1% vs 48.2%).

Compared to countries with the first two developments status, more trial participants in developed countries were able to understand the concept of placebo (24.9% vs 43.4% vs 64%).

Heterogeneity analysis

We selected trial stages (phase I study vs phase II-III studies), tumor or not (cancer vs non-cancer), informed consent recipients (participants themselves vs guardians or caretakers), critical condition (critical illness vs non-critical illness), national development status (least developed countries vs developing countries vs developed countries), and sample size (≥100 vs < 100) as covariates, meta-regression analysis was conducted to explore the sources of inter-study heterogeneity. However, none of the meta-regressions were statistically significant (P>0.05), that is, none of the above covariates can be considered as the source of heterogeneity.

Publication bias

S1 Fig and Table 2 present the publication bias analyses. There was a risk of publication bias for risks and side-effects (P<0.001), the purpose of the study (P<0.001), no therapeutic misconception (P<0.001), benefits of the study(P = 0.009), randomization(P = 0.007), voluntariness (P<0.001), right to withdraw (P<0.001), availability of alternative treatments after withdrawal (P = 0.019), and confidentiality (P = 0.030). Compensation, nature of study, Ability, Placebo, Knowing, and Comprehension were not seen as publication bias (S1 Fig and Table 2).

PowerPoint slide larger image original image Table 2. Begg’s test for publication bias.

Discussion

This updated meta-analysis aimed to estimate the proportion of participants in clinical trials who understand the different components of informed consent. The results showed that most participants understood the fundamental components of informed consent (study nature and compensation, voluntariness, and freedom to withdraw). The understanding of other components, such as the concept of placebo and the ability to name at least one risk, was less satisfactory.

In an early meta-analysis, Falagas et al. [10] analyzed 23 studies published up to 2006 and showed that the understanding rates of the study aim, randomization, voluntariness, withdrawal right, risks, and benefits were 54%, 50%, 47%, 44%, 50%, and 57%, respectively. Another meta-analysis of 47 studies published up to 2010 showed poor understanding of randomization and placebo [11]. A 2015 meta-analysis of 103 trials showed that the understanding rate (in decreasing order) of the withdrawal right, nature of the study, voluntariness, potential benefits, study purpose, risks, confidentiality, alternative treatment if withdrawal, knowing that treatments were being compared, placebo, and randomization were 75.8%, 74.7%, 74.7%, 74.0%, 69.6%, 67.0%, 66.2%, 64.1%, 62.9%, 53.3%, and 52.1%, respectively [12]. The present meta-analysis used the same categories as Tam et al. [12] and included 114 studies (155 datasets) but added comprehension and compensation. In our study, by inclusion of more studies and conducting of more subgroup analyses, we found that the highest proportions of understanding were 97.5% for confidentiality, 95.9% for compensation, 91.4% for the nature of the study, 68.1% for knowing that treatments were being compared, and 67.3% for voluntary nature of participants, while the smallest proportions were for the concept of placebo (4.8%), randomization(39.4%), the ability to name at least one risk (43.4%). The differences might be due to the different studies being included. Still, those results are generally supported by previous studies [10, 11, 58, 60, 90, 132].

The main innovation of the present meta-analysis is the subgroup analyses based on phase I study (vs. phase II-III studies), cancer (vs. non-cancer), participants themselves (vs. guardians or caretakers), and critical illness (vs. non-critical illness). Globally, the improvements could be due to a better consent process and stricter adherence to the GCPs [4, 5], as well as to the evolution of the research methods [133] and improvements in the quality of informed consent [134]. Nevertheless, this is globally supported by a previous study that showed that understanding the risks in general, placebo, and voluntariness had not changed over 30 years [12].

Participants in phase I trials had a lower understanding of compensation, ability to name at least one risk, placebo, voluntariness, availability of other options after withdrawal, and comprehension of informed consent, but a higher understanding of no misconception, risks, benefits, randomization, and withdrawal right. These results are supported by Tam et al. [12], who observed that phase I participants were less likely to understand the study purpose and benefits but were more likely to understand the risks and the right to withdraw. Of note, there are two broad types of phase I studies: studies performed in healthy individuals who volunteer (often for monetary compensation) to test a new drug and individuals with a disease (cancer, for example) who do not have treatment options remaining and who participate in phase I trials hoping to draw some benefits. Such trials are usually performed on a few participants to determine the safety and dose range of drugs. Future studies should examine whether differences exist between these two types.

Cancer trials represent an important part of clinical trials and include a special population of patients who often have poor prognoses with standard treatments. In addition, many cancer drugs are highly toxic and carry a significant risk of grade 3–5 adverse events. In our meta-analysis, these features were represented by cancer patients having a better understanding of no therapeutic misconception, benefits, right to withdraw, and availability of options if withdrawal, but a lower understanding of placebo, knowing that treatments are being compared, and comprehension of informed consent. It could be due to the propensity of cancer patients to want to be saved by the clinical trial, leading to some misconceptions about placebos, treatment comparison, and informed consent [60, 135–137].

The difference in understanding between patients and their guardians or caretakers is well documented. Caretakers can have a more rational approach to dealing with disease than patients [138–140]. In this meta-analysis, the patients had a better understanding of risks, placebo, and randomization but a lower understanding of compensation, the ability to name at least one risk, availability of options after withdrawal, and confidentiality. The results of this review can help clinicians understand the extent to which patients understand the content and meaning of the informed consent form. Once clinicians and researchers understand the barriers and gaps in participants’ knowledge, they can try different approaches to improve the patient experience so that each participant knows what benefits they will gain from the trial and what risks they may have to take.

Patients with critical illnesses represent a special category of participants. The participants either have to make a very quick decision about participation, or their families have to make the same very quick decision in their stead. The time available for explaining the trial is usually limited because of the risk of deterioration of the patient’s condition, and the informed consent process must fit among all the examinations that cannot be delayed to treat the patients in a timely fashion [4, 5, 141–143]. In this meta-analysis, the participants with a critical illness better-understood compensation, knowing that treatments were being compared and the availability of other options after withdrawal, but a lower understanding of the study purpose, risks, benefits, randomization, and confidentiality.

This meta-analysis has limitations. First, it is an updated meta-analysis, and many of the included studies were also included in the original meta-analysis [12], but that was also a strength in that with more aggressive methods and more recent research added to the pool, the current paper was able to determine outcomes that were not found in the earlier analysis. In addition, this meta-analysis only reported the actual situation of informed consent but did not provide data about causal relationships. Future studies should look at the reasons for understanding or not the informed consent process. It will be important for future studies to look for the stimuli that lead to better and worse comprehension of the context of informed consent, making recommendations for how those stimuli can be treated to lead to greater comprehension. Third, the studies meta-analyzed were statistically heterogeneous despite using an appropriate analytic approach (random-effects model) to pool the data and additional measures (sub-group and meta-regression analyses) taken to investigate and explain the sources of statistical heterogeneity. Fourth, publication bias was observed in several components of informed consent, possibly caused by a preference for the publication of studies with positive results. Fifth, only English and Chinese literature were included in this study, and future studies are expected to be analyzed without language restrictions. Finally, these data may not be applicable to neonatal and pediatric trials, as well as some time-critical emergency patient trials, which require parents or relatives to sign informed consent within a short period of time while the child or patient is in a state of severe discomfort.

Conclusions

In conclusion, this updated meta-analysis showed that most participants in clinical trials understood the fundamental components of informed consent: the nature and compensation of the study, the voluntary nature of participation, and the freedom to withdraw at any time. On the other hand, the understanding of other components, such as the concept of placebo and the ability to name at least one risk, was less satisfactory. The findings suggest that investigators should make a greater effort to help research participants achieve a complete understanding of informed consent. The subgroup analysis could also provide some clues regarding the areas of improvement. It would ensure that participants’ decision-making is meaningful and their interests are protected.

Supporting information

S1 Fig. The funnel plot of publication bias.

S1 Table. Description of the included studies.

S2 Table. Quality evaluation of the included studies.

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