Résumé

Objectif

Estimer la proportion des participants à des essais cliniques qui comprennent les différents composants du consentement éclairé.

Méthodes

Les études pertinentes ont été identifiées par une revue systématique de PubMed, Scopus et Google Scholar et par l'examen manuel des listes des références des publications allant jusqu'à octobre 2013. Une méta-analyse des résultats de l'étude a été réalisée à l'aide du modèle à effets aléatoires pour tenir compte de l'hétérogénéité.

Résultats

L'analyse a inclus 103 études évaluant 135 cohortes de participants. La proportion regroupée des participants qui ont compris les composants du consentement éclairé était de 75,8% pour la liberté de se retirer à tout moment, de 74,7% pour la nature de l'étude, de 74,7% pour la nature volontaire de la participation, de 74,0% pour les bénéfices potentiels, de 69,6% pour l'objectif de l'étude, de 67,0% pour les risques et effets indésirables potentiels, de 66,2% pour la confidentialité, de 64,1% pour la disponibilité d'un traitement alternatif en cas de retrait de l'étude, de 62,9% pour la connaissance des traitements évalués, de 53,3% pour le placebo et de 52,1% pour la randomisation. La plupart des participants (62,4%) n'avaient pas d'idées fausses sur le traitement, et 54,9% d'entre eux pouvaient citer au moins un risque. Les analyses de sous-groupe et de métarégression ont identifié des covariables, telles que l'âge, le niveau d'éducation, la maladie grave, la phase et le site de l'étude, qui affectaient significativement la compréhension et indiquaient que la proportion des participants ayant compris le consentement éclairé n'avait pas augmenté sur une période de 30 ans.

Conclusion

La proportion des participants à des essais cliniques, qui ont compris les différents composants du consentement éclairé, variait de 52,1% à 75,8%. Les investigateurs pourraient en faire davantage pour aider les participants à parvenir à la compréhension complète.

Resumen

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.

Resultados

El análisis incluyó 103 estudios que evaluaron 135 cohortes de participantes. La proporción combinada de participantes que entendía los componentes del consentimiento informado fue del 75,8 % para la libertad de retirarse en cualquier momento, 74,7 % para la naturaleza del estudio, 74,7 % para el carácter voluntario de la participación, 74,0 % para los beneficios potenciales, 69,6 % para el propósito del estudio, 67,0 % para los riesgos y efectos secundarios potenciales, 66,2 % para la confidencialidad, 64,1 % para la disponibilidad de tratamiento alternativo si el paciente se retira, 62,9 % para saber que se comparaban tratamientos, 53,3 % para el placebo y 52,1 % para la aleatorización. La mayoría de los participantes, el 62,4 %, no tenía una idea equivocada sobre la terapia y el 54,9 % no fue capaz de nombrar al menos un riesgo. Los análisis de subgrupos y la metarregresión identificaron covariables, como edad, nivel educativo, enfermedad crítica, fase de estudio y ubicación, que influían considerablemente en la comprensión y señalaron que la proporción de participantes que entendía el consentimiento informado no había aumentado en 30 años.

Conclusión

La proporción de participantes de ensayos clínicos que entendía los diferentes componentes del consentimiento informado varió del 52,1 % al 75,8 %. Los investigadores podrían realizar esfuerzos mayores para ayudar a los pacientes a lograr una comprensión total.

ملخص

الغرض

تقدير نسبة المشاركين في التجارب السريرية الذين يفهمون العناصر المختلفة للموافقة المستنيرة.

الطريقة

تم تحديد الدراسات ذات الصلة عن طريق استعراض منهجي لقواعد بيانات PubMed وScopus وGoogle Scholar وعن طريق استعراض يدوي لقوائم المراجع الخاصة بالمنشورات حتى تشرين الأول/أكتوبر 2013. وتم إجراء تحليل تال لنتائج الدراسة باستخدام نموذج التأثيرات العشوائية لوضع التغايرية في الحسبان.

النتائج

اشتمل التحليل على 103 دراسة تقوم بتقييم 135 مجموعة من المشاركين. وكانت النسبة المجمعة للمشاركين الذين فهموا عناصر الموافقة المستنيرة 75.8 % بالنسبة لحرية الانسحاب في أي وقت و74.7 % بالنسبة لطبيعة الدراسة و74.7 % بالنسبة لطبيعة المشاركة الطوعية و74.0 % بالنسبة للفوائد المحتملة و69.6 % بالنسبة لغرض الدراسة و67.0 % بالنسبة للمخاطر والآثار الجانبية المحتملة و66.2 % بالنسبة لسرية المعلومات و64.1 % بالنسبة لإتاحة العلاج البديل في حالة الانسحاب من التجربة السريرية و62.9 % بالنسبة لمعرفة إجراء مقارنات بين العلاجات و53.3 % بالنسبة للدواء الوهمي و52.1 % بالنسبة للتوزيع العشوائي. ولم يكن لدى معظم المشاركين، 62.4 %، مفاهيم علاجية خاطئة واستطاع 54.9 % تحديد خطر واحد على الأقل. وحددت تحليلات الفئات الفرعية وتحليلات الارتداد التالي المتغيرات المصاحبة، مثل السن والمستوى التعليمي والاعتلالات الحرجة ومرحلة الدراسة وموقعها، والتي أثرت بشكل كبير على الفهم وأشارت إلى أن نسبة المشاركين الذين فهموا الموافقة المستنيرة لم تشهد زيادة على مدار 30 سنة.

الاستنتاج

تراوحت نسبة المشاركين في التجارب السريرية الذين فهموا العناصر المختلفة للموافقة المستنيرة من 52.1 % إلى 75.8 %. ويستطيع الخبراء تقديم المزيد لمساعدة المشاركين في تحقيق الفهم الكامل.

摘要

目的

估算临床试验中参与者理解知情同意不同组成部分的比例。

方法

系统回顾PubMed、Scopus和Google Scholar来识别相关研究。使用随机影响模型执行研究结果荟萃分析，以便将异质性考虑在内。

结果

分析包括评估135组参与者的103项研究。参与者理解知情同意组成部分的混合比例为：75.8%理解随时退出的自由，74.7%理解研究的性质，74.7%理解参与的自愿性质，74.0%理解潜在收益，69.6%理解研究目的，67.0%理解潜在的风险和副作用，66.2%理解保密性，64.1%理解退出情况下替代治疗的提供，62.9%知道治疗正在接受比较，53.3%理解安慰剂，52.1%理解随机化。大多数参与者（62.4%）没有治疗误区，54.9%能够说出至少一个风险。子群和meta回归分析识别出年龄、教育水平、重要疾病、研究分期和位置等对理解产生显著影响的协变量，并指明30多年来参与者理解知情同意的比例并没有增加。

结论

临床试验参与者理解知情同意各个组成的比例为52.1%到75.8%不等。研究者可以做更多的工作来帮助参与者完全理解各个组成部分。

Резюме

Цель

Определить долю участников клинических исследований, которые понимают различные детали информированного согласия.

Методы

Соответствующие исследования были выявлены посредством систематического обзора PubMed, Scopus и Google Scholar, а также путем просмотра вручную библиографических списков публикаций, изданных до октября 2013 г. Мета-анализ результатов исследований проводился с помощью модели со случайными эффектами для учета разнородности.

Результаты

Анализ включал 103 исследования с оценкой 135 групп участников. Общие доли участников, которые понимали следующие компоненты информированного согласия, составляли: 75,8% — о праве прекратить участие в исследовании в любое время, 74,7% — о природе исследования, 74,7% — о добровольном участии, 74,0% — о потенциальной пользе, 69,6 — о целях исследования, 67,0% — о потенциальных рисках и нежелательных явлениях, 66,2% — о конфиденциальности, 64,1% — о наличии альтернативного лечения при выходе из исследования, 62,9% — о знании сравнения терапий, 53,3% — о плацебо и 52,1% — о рандомизации. Большинство участников, а именно 62,4%, имели правильное представление о терапии и 54,9% могли назвать по меньшей мере один риск. С помощью анализа данных в подгруппах и мета-регрессионного анализа были определены независимые переменные, такие как возраст, уровень образования, критическое заболевание, место проведения и фаза исследования, которые оказывали значительное влияние на понимание и указывали на то, что доля участников, понимающих информированное согласие, не увеличилась за 30 лет.

Вывод

Доля участников клинических исследований, которые понимали различные компоненты информированного согласия, варьировалась в диапазоне от 52,1% до 75,8%. Исследователи могли бы предпринять дополнительные меры, чтобы участники исследований в более полной мере поняли суть информированного согласия.

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.¹1 Grodin MA, Annas GJ. Legacies of Nuremberg. Medical ethics and human rights. JAMA. 1996 Nov 27;276(20):1682–3. doi: http://dx.doi.org/10.1001/jama.1996.03540200068035 PMID: 8922458
https://doi.org/10.1001/jama.1996.035402... ^,22 Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA. 2000 May 24-31;283(20):2701–11. doi: http://dx.doi.org/10.1001/jama.283.20.2701 PMID: 10819955
https://doi.org/10.1001/jama.283.20.2701... Within its ethical and legal foundations,³3 Annas GJ. Doctors, patients, and lawyers–two centuries of health law. N Engl J Med. 2012 Aug 2;367(5):445–50. doi: http://dx.doi.org/10.1056/NEJMra1108646 PMID: 22853015
https://doi.org/10.1056/NEJMra1108646... 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.⁴4 Jefford M, Moore R. Improvement of informed consent and the quality of consent documents. Lancet Oncol. 2008 May;9(5):485–93. doi: http://dx.doi.org/10.1016/S1470-2045(08)70128-1 PMID: 18452859
https://doi.org/10.1016/S1470-2045(08)70... ^,55 Will JF. A brief historical and theoretical perspective on patient autonomy and medical decision making: Part II: The autonomy model. Chest. 2011 Jun;139(6):1491–7. doi: http://dx.doi.org/10.1378/chest.11-0516 PMID: 21652559
https://doi.org/10.1378/chest.11-0516... Obtaining written informed consent from participants before enrolment in a study is an internationally accepted standard.⁶6 Wendler D. How to enroll participants in research ethically. JAMA. 2011 Apr 20;305(15):1587–8. doi: http://dx.doi.org/10.1001/jama.2011.421 PMID: 21505137
https://doi.org/10.1001/jama.2011.421... ^–1010 Boga M, Davies A, Kamuya D, Kinyanjui SM, Kivaya E, Kombe F, et al. Strengthening the informed consent process in international health research through community engagement: The KEMRI-Wellcome Trust Research Programme Experience. PLoS Med. 2011 Sep;8(9):e1001089. doi: http://dx.doi.org/10.1371/journal.pmed.1001089 PMID: 21931539
https://doi.org/10.1371/journal.pmed.100...

Five concepts must be considered in establishing informed consent: voluntariness, capacity, disclosure, understanding and decision.¹¹11 del Carmen MG, Joffe S. Informed consent for medical treatment and research: a review. Oncologist. 2005 Sep;10(8):636–41. doi: http://dx.doi.org/10.1634/theoncologist.10-8-636 PMID: 16177288
https://doi.org/10.1634/theoncologist.10... ^,1212 Beauchamp TL, Childress JF. Principles of biomedical ethics. New York: Oxford University Press; 2001. 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.¹³13 Weijer C, Grimshaw JM, Eccles MP, McRae AD, White A, Brehaut JC, et al.; Ottawa Ethics of Cluster Randomized Trials Consensus Group. The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials. PLoS Med. 2012;9(11):e1001346. doi: http://dx.doi.org/10.1371/journal.pmed.1001346 PMID: 23185138
https://doi.org/10.1371/journal.pmed.100... 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.¹¹11 del Carmen MG, Joffe S. Informed consent for medical treatment and research: a review. Oncologist. 2005 Sep;10(8):636–41. doi: http://dx.doi.org/10.1634/theoncologist.10-8-636 PMID: 16177288
https://doi.org/10.1634/theoncologist.10... ^,1212 Beauchamp TL, Childress JF. Principles of biomedical ethics. New York: Oxford University Press; 2001.

The quality of informed consent in clinical research is determined by the extent to which participants understand the process of informed consent.¹⁴14 Sreenivasan G. Does informed consent to research require comprehension? Lancet. 2003 Dec 13;362(9400):2016–8. doi: http://dx.doi.org/10.1016/S0140-6736(03)15025-8 PMID: 14683665
https://doi.org/10.1016/S0140-6736(03)15... Understanding plays a pivotal role in clinical research because it directly affects how ethical principles are applied in practice.¹⁵15 Lad PM, Dahl R. Audit of the informed consent process as a part of a clinical research quality assurance program. Sci Eng Ethics. 2014 Jun;20(2):469–79. doi: http://dx.doi.org/10.1007/s11948-013-9461-4 PMID: 23975172
https://doi.org/10.1007/s11948-013-9461-... ^–1717 Bhutta ZA. Beyond informed consent. Bull World Health Organ. 2004 Oct;82(10):771–7. PMID: 15643799 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.¹⁸18 Falagas ME, Korbila IP, Giannopoulou KP, Kondilis BK, Peppas G. Informed consent: how much and what do patients understand? Am J Surg. 2009 Sep;198(3):420–35. doi: http://dx.doi.org/10.1016/j.amjsurg.2009.02.010 PMID: 19716887
https://doi.org/10.1016/j.amjsurg.2009.0... Another systemic review, which included data up to 2010, compared only the quality of informed consent in developing and developed countries.¹⁹19 Mandava A, Pace C, Campbell B, Emanuel E, Grady C. The quality of informed consent: mapping the landscape. A review of empirical data from developing and developed countries. J Med Ethics. 2012 Jun;38(6):356–65. doi: http://dx.doi.org/10.1136/medethics-2011-100178 PMID: 22313664
https://doi.org/10.1136/medethics-2011-1... 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 meta-analysis of the data available.

Methods

We conducted a literature search of PubMed and Scopus using the following terms: “informed consent[mh] AND (comprehension[mh] OR decision making[mh] OR knowledge[mh] OR perception[mh] OR communication[mh] OR understanding) AND (randomized controlled trials as topic[mh] OR clinical trial as topic[mh])”. In addition, in a simple search of Scopus, we used: “allintitle: understanding OR comprehension OR knowledge OR decision OR perception OR communication “informed consent”.” In Google Scholar, we used the keywords “informed consent” as the exact phrase and “understanding, comprehension, knowledge, decision, perception, communication” with the option with at least one of the words and selected “where my words occur in the title of the article”. The search strategy was developed as previously described.²⁰20 Aromataris E, Riitano D. Constructing a search strategy and searching for evidence. A guide to the literature search for a systematic review. Am J Nurs. 2014 May;114(5):49–56. doi: http://dx.doi.org/10.1097/01.NAJ.0000446779.99522.f6 PMID: 24759479
https://doi.org/10.1097/01.NAJ.000044677... The searches covered all data entered up to 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 consent¹1 Grodin MA, Annas GJ. Legacies of Nuremberg. Medical ethics and human rights. JAMA. 1996 Nov 27;276(20):1682–3. doi: http://dx.doi.org/10.1001/jama.1996.03540200068035 PMID: 8922458
https://doi.org/10.1001/jama.1996.035402... ^,22 Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA. 2000 May 24-31;283(20):2701–11. doi: http://dx.doi.org/10.1001/jama.283.20.2701 PMID: 10819955
https://doi.org/10.1001/jama.283.20.2701... and at least one of the following components of the informed consent process:⁸8 Rivera R, Borasky D, Rice R, Carayon F, Wong E. Informed consent: an international researchers’ perspective. Am J Public Health. 2007 Jan;97(1):25–30. doi: http://dx.doi.org/10.2105/AJPH.2005.081604 PMID: 17138913
https://doi.org/10.2105/AJPH.2005.081604... ^,2121 Protection of human subjects. Code Fed Requl Public Welfare. Washington: U.S. Department of Health and Human Services; 1995 Oct 1;Title 4s: sections 46-101 to 46-409. 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. 1.²²22 Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000 Apr 19;283(15):2008–12. doi: http://dx.doi.org/10.1001/jama.283.15.2008 PMID: 10789670
https://doi.org/10.1001/jama.283.15.2008...

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_Supplements_for_Three_decades_of_participants_understanding_of_informed_consent_in_clinical_trials_a_systematic_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 I² 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 < 0.05.²³23 Sedgwick P. Meta-analyses: heterogeneity and subgroup analysis. BMJ. 2013 June 24;346 jun24 2:f4040. doi: http://dx.doi.org/10.1136/bmj.f4040
https://doi.org/10.1136/bmj.f4040... 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.²⁴24 Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Comparison of two methods to detect publication bias in meta-analysis. JAMA. 2006 Feb 8;295(6):676–80. doi: http://dx.doi.org/10.1001/jama.295.6.676 PMID: 16467236
https://doi.org/10.1001/jama.295.6.676... When publication bias was present, we used Duvall and Tweedie’s trim-and-fill method to enhance symmetry by adjusting for studies that appeared to be missing.²⁵25 Duval S, Tweedie R. Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000 Jun;56(2):455–63. doi: http://dx.doi.org/10.1111/j.0006-341X.2000.00455.x PMID: 10877304
https://doi.org/10.1111/j.0006-341X.2000... ^–2727 Kaufert JM, O’Neil J. Culture, power and informed consent: the impact of Aboriginal health interpreters on decision-making. In: Coburn D, D’Arcy C, Torrance G, editors. Health and Canadian society: sociological perspectives. Toronto: University of Toronto Press; 1998. 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.²⁸28 Ellis RD, Sagara I, Durbin A, Dicko A, Shaffer D, Miller L, et al. Comparing the understanding of subjects receiving a candidate malaria vaccine in the United States and Mali. Am J Trop Med Hyg. 2010 Oct;83(4):868–72. doi: http://dx.doi.org/10.4269/ajtmh.2010.10-0062 PMID: 20889881
https://doi.org/10.4269/ajtmh.2010.10-00... ^–130130 Verheggen FW, Jonkers R, Kok G. Patients’ perceptions on informed consent and the quality of information disclosure in clinical trials. Patient Educ Couns. 1996 Nov;29(2):137–53. doi: http://dx.doi.org/10.1016/0738-3991(96)00859-2 PMID: 9006231
https://doi.org/10.1016/0738-3991(96)008... 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 countries – as classified by the World Bank¹³¹131 Country and lending groups [Internet]. Washington: World Bank; 2014. Available from: http://data.worldbank.org/about/country-and-lending-groups [cited 2014 Dec 12].
http://data.worldbank.org/about/country-... – 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).

Understanding of informed consent

The number of data sets that covered each component of informed consent is shown in Appendix B (available at: https://www.researchgate.net/publication/270506278_Online_Only_Supplements_for_Three_decades_of_participants_understanding_of_informed_consent_in_clinical_trials_a_systematic_review_and_meta-analysis). Understanding of freedom to withdraw at any time was investigated in the largest number of studies (n = 79), whereas understanding of placebo was investigated in the smallest number (n = 15). Our analysis showed some variation in the proportion of participants who understood different components of informed consent. The highest proportions were 75.8% (95% CI: 70.6–80.3) for freedom to withdraw from the study at any time, 74.7% (95% CI: 68.8–79.8) for the nature of study, 74.7% (95% CI: 67.9–80.5) for the voluntary nature of participation and 74.0% (95% CI: 65.0–81.3) for potential benefits (Fig. 2 and Appendix B). Lower proportions were 69.6% (95% CI: 63.5–75.1) for the purpose of the study, 67.0% (95% CI: 57.4–75.4) for potential risks and side-effects, 66.2% (95% CI: 55.3–75.7) for confidentiality, 64.1% (95% CI: 53.7–73.4) for the availability of alternative treatment if withdrawn and 62.9% (95% CI: 45.5–77.5) for knowing that treatments were being compared. In addition, 62.4% (95% CI: 50.1–73.2) had no therapeutic misconceptions. The lowest proportions were 54.9% (95% CI: 43.3–65.0) for naming at least one risk, followed by 53.3% (95% CI: 38.4–67.6) for understanding of placebo and 52.1% (95% CI: 41.3–62.7) for understanding of randomization.

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 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.¹³²132 Idänpäänheikkilä JE. WHO guidelines for good clinical practice (GCP) for trials on pharmaceutical products: responsibilities of the investigator. Ann Med. 1994 Apr;26(2):89–94. doi: http://dx.doi.org/10.3109/07853899409147334 PMID: 8024733
https://doi.org/10.3109/0785389940914733... 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_Supplements_for_Three_decades_of_participants_understanding_of_informed_consent_in_clinical_trials_a_systematic_review_and_meta-analysis).

Discussion

Obtaining informed consent from participants in clinical research is essential because it promotes their welfare and ensures their rights.⁹9 World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013 Nov 27;310(20):2191–4. doi: http://dx.doi.org/10.1001/jama.2013.281053 PMID: 24141714
https://doi.org/10.1001/jama.2013.281053... ^,133133 Moreno J, Caplan AL, Wolpe PR. Updating protections for human subjects involved in research. Project on Informed Consent, Human Research Ethics Group. JAMA. 1998 Dec 9;280(22):1951–8. doi: http://dx.doi.org/10.1001/jama.280.22.1951 PMID: 9851484
https://doi.org/10.1001/jama.280.22.1951... 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 review¹⁸18 Falagas ME, Korbila IP, Giannopoulou KP, Kondilis BK, Peppas G. Informed consent: how much and what do patients understand? Am J Surg. 2009 Sep;198(3):420–35. doi: http://dx.doi.org/10.1016/j.amjsurg.2009.02.010 PMID: 19716887
https://doi.org/10.1016/j.amjsurg.2009.0... 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 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.¹⁸18 Falagas ME, Korbila IP, Giannopoulou KP, Kondilis BK, Peppas G. Informed consent: how much and what do patients understand? Am J Surg. 2009 Sep;198(3):420–35. doi: http://dx.doi.org/10.1016/j.amjsurg.2009.02.010 PMID: 19716887
https://doi.org/10.1016/j.amjsurg.2009.0... ^,1919 Mandava A, Pace C, Campbell B, Emanuel E, Grady C. The quality of informed consent: mapping the landscape. A review of empirical data from developing and developed countries. J Med Ethics. 2012 Jun;38(6):356–65. doi: http://dx.doi.org/10.1136/medethics-2011-100178 PMID: 22313664
https://doi.org/10.1136/medethics-2011-1... ^,134134 de Melo-Martín I, Ho A. Beyond informed consent: the therapeutic misconception and trust. J Med Ethics. 2008 Mar;34(3):202–5. doi: http://dx.doi.org/10.1136/jme.2006.019406 PMID: 18316464
https://doi.org/10.1136/jme.2006.019406... ^–137137 Ballard HO, Shook LA, Desai NS, Anand KJ. Neonatal research and the validity of informed consent obtained in the perinatal period. J Perinatol. 2004 Jul;24(7):409–15. doi: http://dx.doi.org/10.1038/sj.jp.7211142 PMID: 15152271
https://doi.org/10.1038/sj.jp.7211142... 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.¹³⁸138 Miller FG, Joffe S. Phase 1 oncology trials and informed consent. J Med Ethics. 2013 Dec;39(12):761–4. doi: http://dx.doi.org/10.1136/medethics-2012-100832 PMID: 23161617
https://doi.org/10.1136/medethics-2012-1... ^–140140 Flory J, Emanuel E. Interventions to improve research participants’ understanding in informed consent for research: a systematic review. JAMA. 2004 Oct 6;292(13):1593–601. doi: http://dx.doi.org/10.1001/jama.292.13.1593 PMID: 15467062
https://doi.org/10.1001/jama.292.13.1593...

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,¹⁹19 Mandava A, Pace C, Campbell B, Emanuel E, Grady C. The quality of informed consent: mapping the landscape. A review of empirical data from developing and developed countries. J Med Ethics. 2012 Jun;38(6):356–65. doi: http://dx.doi.org/10.1136/medethics-2011-100178 PMID: 22313664
https://doi.org/10.1136/medethics-2011-1... 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.¹⁴¹141 Hyder AA, Rattani A, Krubiner C, Bachani AM, Tran NT. Ethical review of health systems research in low- and middle-income countries: a conceptual exploration. Am J Bioeth. 2014;14(2):28–37. doi: http://dx.doi.org/10.1080/15265161.2013.868950 PMID: 24521334
https://doi.org/10.1080/15265161.2013.86... 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 open-ended 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.¹⁴²142 Cargan L. Doing social research. Lanham: Rowman and Littlefield Publishers; 2007. 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.¹⁴³143 Takemura Y, Sakurai Y, Yokoya S, Otaki J, Matsuoka T, Ban N, et al. Open-ended questions: are they really beneficial for gathering medical information from patients? Tohoku J Exp Med. 2005 Jun;206(2):151–4. doi: http://dx.doi.org/10.1620/tjem.206.151 PMID: 15888971
https://doi.org/10.1620/tjem.206.151...

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 time¹⁴⁴144 Faralli C. Informed consent in medicine: ethical and juridical aspects. Milan: Salute e Società; 2013. and many attempts made to improve the quality of informed consent.¹⁴⁵145 Isles AF. Understood consent versus informed consent: a new paradigm for obtaining consent for pediatric research studies. Front Pediatr. 2013;1:38. doi: http://dx.doi.org/10.3389/fped.2013.00038 PMID: 24400284
https://doi.org/10.3389/fped.2013.00038... 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 forms and extended discussions led to significant increases in understanding whereas multimedia approaches did not.¹⁴⁶146 Nishimura A, Carey J, Erwin PJ, Tilburt JC, Murad MH, McCormick JB. Improving understanding in the research informed consent process: a systematic review of 54 interventions tested in randomized control trials. BMC Med Ethics. 2013;14(1):28. doi: http://dx.doi.org/10.1186/1472-6939-14-28 PMID: 23879694
https://doi.org/10.1186/1472-6939-14-28... 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.¹⁴⁰140 Flory J, Emanuel E. Interventions to improve research participants’ understanding in informed consent for research: a systematic review. JAMA. 2004 Oct 6;292(13):1593–601. doi: http://dx.doi.org/10.1001/jama.292.13.1593 PMID: 15467062
https://doi.org/10.1001/jama.292.13.1593... ^,146146 Nishimura A, Carey J, Erwin PJ, Tilburt JC, Murad MH, McCormick JB. Improving understanding in the research informed consent process: a systematic review of 54 interventions tested in randomized control trials. BMC Med Ethics. 2013;14(1):28. doi: http://dx.doi.org/10.1186/1472-6939-14-28 PMID: 23879694
https://doi.org/10.1186/1472-6939-14-28... ^–148148 Terranova G, Ferro M, Carpeggiani C, Recchia V, Braga L, Semelka RC, et al. Low quality and lack of clarity of current informed consent forms in cardiology: how to improve them. JACC Cardiovasc Imaging. 2012 Jun;5(6):649–55. doi: http://dx.doi.org/10.1016/j.jcmg.2012.03.007 PMID: 22698536
https://doi.org/10.1016/j.jcmg.2012.03.0...

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.¹⁴⁹149 Mårtenson EK, Fägerskiöld AM. A review of children’s decision-making competence in health care. J Clin Nurs. 2008 Dec;17(23):3131–41. doi: http://dx.doi.org/10.1111/j.1365-2702.2006.01920.x PMID: 18005126
https://doi.org/10.1111/j.1365-2702.2006... ^,150150 Kluge EH. Informed consent by children: the new reality. CMAJ. 1995 May 1;152(9):1495–7. PMID: 7728701 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,¹⁵¹151 Cox DR. Combination of data. In: Kotz S, Johnson NL, Read CB, Balakrishnan N, Vidakovic B, editors. Encyclopedia of statistical sciences. 2nd ed. Hoboken: John Wiley & Sons; 2006.pp. 1074–81. 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.¹⁵²152 Baker WL, White CM, Cappelleri JC, Kluger J, Coleman CI; Health Outcomes, Policy, and Economics (HOPE) Collaborative Group. Understanding heterogeneity in meta-analysis: the role of meta-regression. Int J Clin Pract. 2009 Oct;63(10):1426–34. doi: http://dx.doi.org/10.1111/j.1742-1241.2009.02168.x PMID: 19769699
https://doi.org/10.1111/j.1742-1241.2009... ^–154154 Ioannidis JP, Patsopoulos NA, Rothstein HR. Reasons or excuses for avoiding meta-analysis in forest plots. BMJ. 2008 Jun 21;336(7658):1413–5. doi: http://dx.doi.org/10.1136/bmj.a117 PMID: 18566080
https://doi.org/10.1136/bmj.a117...

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.

References

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