Ethics and consent in randomized clinical trial integrity: A scoping systematic review

Abstract

Objectives

This scoping systematic review aimed to collate and synthesize available evidence on research ethics and consent aspects related to research integrity standards in RCTs. Prospective registration (https://osf.io/gxryb).

Materials and methods

We searched PubMed and Scopus databases from January 2018 to August 2023, using combinations of terms related to research ethics, approval, and informed consent. We included full academic articles relevant to the scope of the review without language restriction, including primary research articles, systematic reviews, scoping reviews, and narrative reviews. Two teams of four reviewers independently assessed the full text to select articles and extract data, performing the tasks independently and any disagreements were resolved through arbitration. A descriptive synthesis of the included articles main characteristics and findings were performed.

Results

Sixty-nine articles were selected, covering RCT-related ethics and consent issues in 141 countries, including 89 (63%) low or middle-income ones. The extracted data fell into nine domains: general issues (30 articles; 43%), journals’ instructions and policies (one article; 1.4%), research institutions and funders’ policies (three articles; 4.3%), ethics committee regulations (five articles; 7.2%), ethics committee evaluation and approval (12 articles; 17%), informed consent and related procedures (six articles; 8.7%), monitoring of trials for compliance (three articles; 4.3%), post-publication concerns on ethics and consent (five articles; 7.2%), and recommendations for future research (four articles; 5.8%).

Conclusions

The key areas include standardization of ethics committee approval processes and enhancement of informed consent procedures. There were notable deficiencies in trial registration and reporting concerning ethics and consent. The observed variability in ethics and consent practices across RCTs globally needs to be addressed through an international expert consensus.

Resumen

Objetivos

Esta revisión sistemática tuvo como objetivo recopilar y sintetizar la evidencia disponible sobre la relación entre los aspectos éticos de la investigación y las condiciones del consentimiento informado con los estándares de integridad de la investigación en ECA.

Materiales y métodos

Tras el registro del protocolo (https://osf.io/gxryb), se realizaron búsquedas en las bases de datos PubMed y Scopus desde enero de 2018 hasta agosto de 2023, utilizando combinaciones de términos relacionados con la ética de la investigación, la aprobación y el consentimiento informado. Se incluyeron artículos académicos completos relevantes para el alcance de la revisión sin restricción de idioma, incluyendo artículos de investigación primaria, revisiones sistemáticas y revisiones narrativas. Dos equipos de cuatro revisores evaluaron de forma independiente el texto completo para seleccionar los artículos y extraer los datos, realizando las tareas de forma independiente y cualquier desacuerdo se resolvió mediante arbitraje. Se realizó una síntesis descriptiva de las principales características y hallazgos de los artículos incluidos.

Resultados

Se seleccionaron 69 artículos que abordaban cuestiones éticas y de consentimiento relacionadas con los ECA en 141 países, incluyendo 89 (63%) de ingresos bajos o medios. Los datos extraídos se dividieron en nueve áreas: cuestiones generales (30 artículos; 43%), instrucciones y políticas de las revistas (un artículo; 1,4%), políticas de las instituciones de investigación y agencias financiadoras (tres artículos; 4,3%), reglamentos de los comités de ética (cinco artículos; 7,2%), evaluación y aprobación de los comités de ética (12 artículos; 17%), consentimiento informado y procedimientos relacionados (seis artículos; 8,7%), monitorización del cumplimiento de los ensayos (tres artículos; 4,3%), inquietudes posteriores a la publicación sobre ética y consentimiento (cinco artículos; 7,2%) y recomendaciones para futuras investigaciones (cuatro artículos; 5,8%).

Conclusiones

Los puntos clave incluyeron la estandarización de los procesos de aprobación de los comités de ética y la mejora de los procedimientos de obtención del consentimiento informado. Se observaron deficiencias notables en el registro y la notificación de ensayos clínicos en relación con la ética y el consentimiento. La variabilidad observada en las prácticas éticas y de consentimiento en los ECA a nivel mundial debe abordarse mediante un consenso internacional de expertos.

Introduction

Randomized clinical trials (RCTs), regarded as the gold standard evidence source to inform clinical practice,¹ are incorporated in healthcare decision-making through meta-analyses, systematic reviews, practice committee opinions, societal guidelines, etc. Drug and device approval processes (e.g., by the U.S. Food and Drug Administration) heavily rely on data derived from RCTs.^2,3 Consequently, the integrity of RCTs has a direct and substantial impact on healthcare. Over the years, the perceived usefulness of RCTs has been challenged in part on account of concerns related to transparency.⁴ There has also been a rise in the number of retracted RCT articles.^5,6 Integrity breaches jeopardize the RCT findings, potentially compromising patient safety and well-being, not just the validity of the scientific record.

Approval of research and informed consent by the Ethics Committee is fundamental to the integrity of RCTs.^7,8 Ethical principles, such as respect, beneficence, non-maleficence and justice, ensure the protection of trial participants’ rights, minimizing potential risks and maximizing benefits.⁹ Institutions conducting RCTs must, by law, foster an environment that promotes ethical conduct, through rigorous oversight. Exactly how they should achieve this has been the subject of research but no RCT-specific guidance or overview exists. Few systematic reviews have attempted to address ethics and consent issues in RCTs.^10–12 A previous statement on RCT integrity emphasized that ethics approval should be obtained for all trials, including those using de-identified data, and informed consent should be developed with patient (or their representative) and public involvement.¹³

Recognizing the importance of research ethics and consent in the integrity of RCTs, and the gaps that exist in evidence synthesis, we conducted a systematic scoping review to collate and synthesize available evidence with a view to providing an information base for developing integrity standards in RCTs.

Methods

This scoping review was prospectively registered (Center for Open Science, https://osf.io/gxryb), conducted using a recommended methodology,^3,14 and reported according to the PRISMA-ScR guidelines¹⁵ (Appendix S1).

Search strategy, data sources and study selection

Two reviewers (FAB and JPR) searched PubMed and Scopus databases for relevant articles on August 21st, 2023, using combinations of the following terms: “ethic*”, “research”, “approval”, and “informed consent” (Appendix S2). Those terms were developed through an iterative process, including several pilot searches to capture various research ethics issues and consent implementation aspects concerning integrity standards in human clinical trials. No language restriction was applied to the search. We only included articles within the last five years (2018–2023). An online tool specifically designed to help with systematic literature review (https://www.rayyan.ai/) was used to screen articles and remove duplicates.

We included any full academic article relevant to the scope of this review, including primary research articles, systematic reviews, scoping reviews, and narrative reviews. We excluded editorials, correspondence, and conference abstracts. After removing duplicates, three reviewers (FAB, ABC, and JPR) screened titles and abstracts of retrieved articles for potential inclusion. Four reviewers (FAB, JPR, MAE, and MMR) worked in two teams to independently assess the full text of potentially suitable articles for inclusion or exclusion, with each article independently assessed by at least two reviewers. One senior reviewer (ABC, MMD, or MF) assessed any disagreement between two reviewers and arbitrated to reach a final decision. Another senior reviewer (KSK) independently examined the included articles list. Any disagreement between KSK and the other senior reviewers was resolved through consensus. Reasons for article exclusion included: out of scope of review question, not related to ethics and consent, and not applicable to RCTs.

Data extraction and categorization

Four senior reviewers (KSK, ABC, MMD, and MF) agreed upon the items to be extracted from the included articles. Four reviewers (ABC, MMD, KSK, and FAB) constructed the data extraction sheet (Appendix S3). Four reviewers (FAB, JPR, MAE, and MMR) worked in two teams of two reviewers each to independently extract data from included articles. One senior reviewer (ABC, MMD, or MF) examined the extracted data and resolved any disagreement between the independent reviewers through arbitration. Then, two reviewers (KSK and ABC) examined the extracted articles’ main findings, and categorized them into domains. The nine domains were (a) general issues; (b) journals’ instructions and policies; (c) research institutions and funders’ policies; (d) ethics committee regulations; (e) ethics committee evaluation and approval; (f) informed consent and related procedures; (g) monitoring of trials for compliance; (h) post-publication concerns on ethics and consent; (i) and recommendations for future research. One reviewer (MAE) retrieved the study design, focus, and main finding from the data extraction sheet into a separate supplementary file (Appendix S4) and categorized the findings under the proposed domains. All other reviewers (KSK, PC, ABC, MMD, MF, FAB, JPR, MNN, and MMR) reviewed the retrieved and categorized findings.

Data synthesis

We used Posit Cloud¹⁶ to perform a descriptive analysis of the included articles’ main characteristics including the study design, the year of publication, the topic being addressed, and the study domain. Continuous data was expressed as median (range) and binary data was expressed as n (%). The main findings of each article were tabulated.

Results

Study selection

Database search revealed a total of 5128 citations (976 citations from PubMed and 4152 citations from Scopus) (Fig. 1). We assessed the titles and abstracts of 3933 citations after automatic removal of duplicates using Rayyan. We identified and fully assessed 105 articles potentially related to the scope of this review within the last five years. We finally included 69 articles^12,17–84 (Appendix S4) and excluded a total of 36 (27 articles not related to RCTs,^85–111 three articles not related to research ethics,^112–114 three articles without qualitative or quantitative data,^115–117 two articles manually identified as duplicates,^47,114 and one article¹¹⁸ similar to an included one⁷⁵).

Figure 1.

Flowchart of the literature retrieval process.

Study characteristics and overview of main findings

Table 1 summarizes the main characteristics of the included studies. Most studies (51 articles; 74%) addressed ethics and consent issues related to a certain country or geographical region. Fig. 2 and Table S1 show 141 countries addressed in this scoping review categorized by their income and the relative number of studies per country. Of those 141 countries, 52 (36.9%) were high-income, 64 (45.4%) were middle-income and 25 (17.8%) were low-income countries. Most included studies were cross-sectional (39%), systematic reviews (10%), retrospective analyses (8.7%), and scoping reviews (10%). Fig. S1 shows detailed types and subtypes of included studies. Most studies (57%) did not address a specific health topic. COVID-19 (7.2%), mental health (7.2%), minority health (5.8%), and pediatric health (5.8%) were the most addressed health topics. Fig. S2 shows detailed topics and subtopics of included studies. Most included studies (43%) fell under the “general” domain, while “ethics committee evaluation and approval” (17%) and “informed consent and related procedures” (8.7%) were the next most commonly covered domains (Table 1).

Table 1.

Main characteristics of articles included in the scoping review of ethics and consent in randomized clinical trial integrity.

Characteristic	Number (percent of total 69)
Publications per year	2021 (2018, 2023)
2018	5 (7.2%)
2019	13 (18.8%)
2020	7 (10.1%)
2021	18 (26.1%)
2022	18 (26.1%)
2023	8 (11.6%)
Geographical area covered^a
No restriction	18 (26%)
Country/region specific	51 (74%)
Study design
Cross-sectional	27 (39%)
Systematic review	7 (10%)
Retrospective analysis	6 (8.7%)
Scoping review	5 (7.2%)
Thematic analysis	4 (5.8%)
Consensus	3 (4.3%)
Descriptive analysis	3 (4.3%)
Not mentioned	3 (4.3%)
Systematic scoping review	3 (4.3%)
Desk review	2 (2.9%)
Audit of records	1 (1.4%)
Content analysis (meeting minutes, letters)	1 (1.4%)
Discourse analysis	1 (1.4%)
Literature review	1 (1.4%)
Multiple qualitative methods (interviews)	1 (1.4%)
Secondary analysis (articles)	1 (1.4%)
Health topic addressed
Non-specific	39 (57%)
COVID-19	5 (7.2%)
Mental health	5 (7.2%)
Minority health	4 (5.8%)
Pediatric health	4 (5.8%)
Genomic research	2 (2.9%)
Antibacterial agents	1 (1.4%)
Cancer research	1 (1.4%)
Geriatrics health	1 (1.4%)
HIV	1 (1.4%)
Humanitarian research	1 (1.4%)
Musculoskeletal health	1 (1.4%)
Public health	1 (1.4%)
Smoking; ambulation	1 (1.4%)
Suicide research	1 (1.4%)
Traditional Chinese medicine (TCM)	1 (1.4%)
Domain
A. General	30 (43%)
B. Journals’ instructions and policies	1 (1.4%)
C. Research institutions and funders policies	3 (4.3%)
D. Ethics committee regulations	5 (7.2%)
E. Ethics committee evaluation and approval	12 (17%)
F. Informed consent and related procedures	6 (8.7%)
G. Monitoring of trials for compliance	3 (4.3%)
H. Post-publication concerns on ethics and consent	5 (7.2%)
I. Recommendations for future research	4 (5.8%)

a

See Fig. 2. There were 141 countries covered.

Figure 2.

Countries included in the scoping review of ethics and consent in randomized clinical trial integrity categorized per their income (the color intensity proportionates to the number of related studies; grey (NA) countries were not included. For example, deep blue means high income and coverage by several studies, while light blue means high income and coverage by a low number of studies).

Ethical issues and domains

Appendix S4 shows details, domains, and main findings of the included studies.^12,17–84 In the “general” domain, gaps in research ethics education were identified across various disciplines and regions.^26,64,75 Several studies discussed health issues at country or region levels.^{20,27,44,48,51,52,54,62,74,84} Four studies attempted to establish a consensus or guidelines for research ethics-related issues.^18,31,36,46 Other studies investigated ethical issues of certain health topics including COVID-19,⁶¹ rheumatoid arthritis,⁷² dementia,⁷⁹ and longitudinal health problems.³⁷ Two studies highlighted the importance of research ethics consultation^73,74 and one study acknowledged significant variations in understanding fundamental concepts like equipoise.⁸³

In the “journals’ instructions and policies” domain, published cases of research ethics violations were found to be dominated by prominent biomedical cases, potentially skewing perceptions across disciplines.¹⁹ One study in the “research institutions and funders’ policies” domain highlighted that approaches to fostering research ethics vary between institutions in Thailand, where larger institutions tend to establish more regulatory mechanisms than smaller ones.³³ Another UK study explored novel funding models such as “Plutocratic Proposal” and their ethical implications,²³ and a third study encouraged the implementation of an Ethics and Society Review Board as a precondition for research funding.⁴⁷

The “ethics committee regulations” domain discussed the underrepresentation of community members in Research ethics committees (RECs) in some countries⁶⁶ and resource constraints in others.⁷⁷ REC administrators often play diverse roles beyond administration, yet many lack formal ethics training.²⁸ Progress has been made in incorporating Indigenous knowledge into research ethics governance in some regions, but this is not uniform.⁵⁷ Registered institutional RECs in India outweighed independent ones, with skewed distribution and supervision of regulatory clinical trials among the country states.³⁴

Research on “ethics committee evaluation and approval” processes revealed a complex landscape marked by variability across institutions and countries.^63,81 Committees face criticism for creating research barriers due to lengthy approval times,^60,78 while also struggling with increased workloads, particularly during the COVID-19 pandemic.⁶⁵ Common issues in RCTs applications included inadequate patient information and consent forms, as well as methodological concerns.^32,35,59,68 Recommendations for improvement focused on streamlining processes and balancing participant protection with research facilitation.⁶⁰ There was also a call for capacity building, especially in low and middle-income countries.^29,40 Perspectives on ethics review requirements often differ between committee members, researchers, and community,^49,78 highlighting the need for ongoing dialogue. In international research, differing national practices complicate multi-country study approvals,⁶³ emphasizing the need for greater harmonization of ethics review processes globally.

The “informed consent and related procedures” domain addressed unique ethical challenges in various contexts, such as pediatric critical care,²⁵ acute ischemic stroke trials,⁴⁵ and research involving adolescents in HIV studies.⁴² The COVID-19 pandemic has highlighted the importance of maintaining ethical standards in informed consent, even during health crises.⁵⁸ Electronic informed consent is an emerging area, with specific criteria needed for ethics review.³⁹ There is an ongoing debate about when informed consent might be waived, particularly in pragmatic randomized controlled trials.¹⁷

The “monitoring of trials for compliance” domain highlighted significant discrepancies in the registration and reporting of clinical trials. An audit in the UK found that 20% of trials approved by ethics committees were not registered publicly.⁶⁷ Analysis of COVID-19 studies revealed inconsistencies between different trial registries and a lack of essential ethical information.³⁰ Less than two-thirds of medical theses included in a German study declared obtaining of ethics approval.⁷⁰ Similarly, the “post-publication concerns on ethics” domain highlighted the failure of many published RCTs to report ethical approval and/or informed consent.^{12,41,55,69,71} Key areas identified in the “recommendations for future research” domain included increasing Indigenous-led studies,⁸² improving inclusivity in cancer research designs,⁵⁶ and addressing ethical considerations in emerging fields like brain–computer interface.⁵⁰

Discussion

Main findings

This scoping systematic review captured a diverse array of studies examining research ethics and consent in RCTs. The review's broad scope, evident in its inclusion of 69 articles, covered ethics and consent issues related to RCTs in 141 countries. The literature collated spanning various study designs, health topics, and ethical domains. A notable finding is that approximately two-thirds (63%) of the countries involved in this review were low-middle-income countries. The review revealed several interconnected themes across various domains of ethics and consent in RCTs. General issues highlighted significant gaps in research ethics education, emphasizing the need for more comprehensive training across disciplines and regions. In the realm of ethics committee evaluation and approval, the review uncovered considerable variability in processes, with common challenges including lengthy approval times and increased workloads, particularly during the COVID-19 pandemic. These findings underscore the need to balance rigorous ethical oversight with efficient review procedures. The domain of informed consent brought to light unique challenges in specific contexts, such as pediatric critical care and HIV research involving adolescents. Emerging areas like electronic informed consent and debates around consent waivers in pragmatic RCTs indicate the evolving nature of ethics and consent in the field of research involving humans. Monitoring and compliance issues were evident in the discrepancies found in the registration and reporting of RCTs. Post-publication concerns highlighted a troubling trend of published RCTs failing to adequately report ethics committee approval and informed consent procedures, suggesting a need for more stringent reporting requirements and editorial oversight. Looking to the future, recommendations for further research emphasized the importance of increasing indigenous-led research, improving inclusivity in research designs, and addressing ethical considerations in emerging fields such as brain–computer interface research. These interrelated themes collectively paint a picture of a field grappling with complexity and challenges while striving for improvement and adaptation to the evolving human research landscape.

Strengths and limitations

Our scoping systematic review contained a wide literature search on two electronic databases on various article types ranging from cross-sectional studies and retrospective analysis to systematic reviews. We included a wide range of study articles in this review to collate and synthesize available evidence on research ethics and consent aspects related to research integrity standards in RCTs. We first piloted the search strategy and refined it to target a large number and variety of articles which applied to ethics and consent in RCTs. The full text of screened articles was first piloted for inclusion or exclusion into the review. This made certain that the criteria used for this purpose were reproducible. Subsequently, a minimum of two independent reviewers selected the articles for review which minimizes selection bias. At least two senior researchers resolved any dispute over the selection of articles among the two reviewers to ensure the arbitration of the dispute. Senior reviewers also reviewed the initial list of domains generated in the review for their viability. Sometimes the study design in the original article can be missing, have errors or be confusing.¹¹⁹ We tried to allocate each study to its appropriate study type to the best of our judgment (Fig. S1).

One downside to our review may be that our literature search did not include grey literature. As most RCTs are published as research papers, we targeted only bibliographic databases. We may have missed some articles which were not published as research papers. We have reported our results by its registered methods. While this study's temporal scope was confined to publications from the past five years, this limitation was mitigated by preliminary analyses of earlier literature that demonstrated comparable thematic patterns and findings to those within our selected timeframe. Yet another possible flaw in our review methodology could be that we did not conduct a risk of bias assessment of the articles included in our review. This is less of a concern within our work as no effect size was estimated. A wide range of article types of methodologies were included, so applying a single instrument for quality assessment would not be viable. The purpose of our review was to collate and synthesize the current evidence of articles applied to ethics and consent in RCTs so it can be justified that a quality assessment of the included articles is not required. Scoping reviews typically do not deploy risk of bias assessments.¹²⁰

Implications

Our findings point to the need for improvement in research transparency and accountability. Citizens as stakeholders have a major role in improving ethics and consent in RCTs as open science gains momentum. Journals must also ensure that ethics approval and patients’ consent are documented when reviewing submitted manuscripts for publication. Informed consent is well established as it is a fundamental part of the ethical conduct of RCTs. However, there are still barriers towards its implementation. One barrier to providing informed consent across all diseases is low literacy and numeracy among patients.¹²¹ The risks to generalizability of RCTs are also an ethical concern when marginalized groups are excluded. A study of 15 randomized placebo-controlled secondary prevention trials of statins found that only 23% of 31,683 patients were female.¹²² To improve the ethical standards of RCTs, investigators must have a solid foundation in ethical considerations including diversity issues in the RCT design. The inclusion of studies addressing ethics and consent issues in low-middle income regions reflects an increasing awareness of current challenges in the developing world and a willingness to improve research practices. This trend is encouraging, as it suggests a growing global commitment to enhancing the ethical conduct of RCTs, particularly in regions where research infrastructure and ethical oversight may have been historically less robust.¹²³

We have previously published an international multi-stakeholder consensus statement on RCT integrity,¹³ for which an umbrella review was performed to identify statements and in which stakeholders underwent an anonymized two-round Delphi survey to reach a consensus.¹²⁴ This focused on the transparency required at various stages of their planning, execution and reporting. On the same lines, we intend to use the findings from this review to generate a set of statements for a subsequent consensus on ethics and consent relating to research integrity in RCTs. This review itself supports the need to consolidate the current evidence on research ethics and consent related to research integrity standards in RCTs. Ethics and consent issues occur with frequency on a regular basis, e.g. when clinical trials are raised as a treatment option and when patients are eligible for more than one trial at the time of evaluation.¹²⁵ Investigators have to use their best judgment to reach an independent collegial consensus. Participants have the right to obtain equitable treatment at a given time point.¹²⁵ Currently, the role of the involvement of research ethics committees on these issues needs clarification.

While most countries have guidelines and regulations or laws related to human research,¹²⁶ there has to be an ongoing concern about the protection of participants in RCTs as we face new ailments. More needs to be done for better understanding and wider dissemination of ethics and consent principles to all stakeholders including the public, participants, researchers, members of ethical committees, sponsors, institutions, regulators, charities, funders and policymakers. An international multi-stakeholder consensus on ethics and consent in RCTs deploying the findings of this scoping review can be used as the basis for creating implementation plans and policies at stakeholder institutions and organizations to help promote and protect research integrity.

Conclusion

This scoping review synthesized evidence on research ethics and consent in RCTs, highlighting variability in ethics committee practices and informed consent procedures. Priority areas for improvement include streamlining ethics committee reviews, addressing consent challenges in specific populations, enhancing trial registration and reporting to cover ethics and consent, and strengthening editorial oversight to ensure ethical reporting. The representation of low and middle-income countries indicates growing global awareness of ethics and consent issues in diverse research settings. Moving forward, the research community should focus on harmonizing global research ethics standards while respecting local contexts. There is a need to develop robust RCT integrity policies that cross borders with respect to ethics and consent, reducing exploitation, fostering collaboration, and promoting transparency. By addressing these challenges, we can strengthen the ethical foundation of RCTs, ultimately enhancing the integrity and impact of clinical research worldwide.

CRediT authorship contribution statement

KSK and MF: Conceptualization, project administration. ABC, MMD: Investigation, methodology. FAB, JPR, MNN, MAE, MMR, MMD, MF, KSK, ABC: data curation, validation. MAE: formal analysis. MAE, FAB: writing – original draft, writing – review and editing. KSK, PC, ABC, MMD, MF: supervision.

Funding

This review was conducted without any funding.

Conflict of interest

The authors declare that they have no conflict of interest.

Acknowledgments

M.N.N. is granted a research contract by the Carlos III Research Institute (Juan Rodés JR23/00025).

K.S.K. was funded by the Beatriz Galindo (senior modality) Program grant given to the University of Granada by the Ministry of Science, Innovation and Universities of the Spanish Government.