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The CORBEL matrix on informed consent in clinical studies: a multidisciplinary approach of Research Infrastructures Building Enduring Life-science Services

Abstract

Background

Informed consent forms for clinical research are several and variable at international, national and local levels. According to the literature, they are often unclear and poorly understood by participants. Within the H2020 project CORBEL—Coordinated Research Infrastructures Building Enduring Life-science Services—clinical researchers, researchers in ethical, social, and legal issues, experts in planning and management of clinical studies, clinicians, researchers in citizen involvement and public engagement worked together to provide a minimum set of requirements for informed consent in clinical studies.

Methods

The template was based on a literature review including systematic reviews and guidelines searched on PubMed, Embase, Cochrane Library, NICE, SIGN, GIN, and Clearinghouse databases, and on comparison of templates gathered through an extensive search on the websites of research institutes, national and international agencies, and international initiatives. We discussed the draft versions step-by-step and then we referred to it as the “matrix” to underline its modular character and indicate that it allows adaptation to the context in which it will be used. The matrix was revised by representatives of two international patient groups.

Results

The matrix covers the process of ensuring that the appropriate information, context and setting are provided so that the participant can give truly informed consent. It addresses the key topics and proposes wording on how to clarify the meaning of placebo and of non-inferiority studies, the importance of individual participants’ data sharing, and the impossibility of knowing in advance how the data might be used in future studies. Finally, it presents general suggestions on wording, format, and length of the information sheet.

Conclusions

The matrix underlines the importance of improving the process of communication, its proper conditions (space, time, setting), and addresses the participants’ lack of knowledge on how clinical research is conducted. It can be easily applied to a specific setting and could be a useful tool to identify the appropriate informed consent format for any study. The matrix is mainly intended to support multicentre interventional randomized clinical studies, but several suggestions also apply to non-interventional research.

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Background

Clinical research is an essential component of health care and assistance.

From a broad point of view, research areas, aims, results and effects involve everyone's daily life in different ways. It is therefore important that clinical research addresses the needs and priorities of society [1,2,3].

For many years, in many fields, such as rare diseases, HIV, or breast cancer, persons with a disease and patient associations have taken part in defining research priorities and areas, outcomes, and organizing disease registers or platforms to collect data. Citizens’ and patients’ representatives can take part in ethics committees and boards to decide on research projects to be funded [4,5,6,7]. The participatory production of knowledge where, for example, persons with a disease can define a research question or set up a clinical study design in collaboration with researchers, can increase the value of research [1,2,3].

But for persons with a disease to take an active part in research, they need a cultural environment and conditions favoring dialogue, knowledge exchange, participation and collaboration between people with various expertise and interests.

Participating in a clinical study can also. in some circumstances. provide chances to take an active part in research [7,8,9,10].

With the development of clinical study methods and increasing individual demand for having a voice when participating in a study, new forms of informed consent have been developed, such as electronic and digital informed consents which, despite several limits, can make it easier for participants to decide, for example, whether and when to consent to sharing pseudonymised data, or biosamples [11].

However, in order to make a conscious and informed decision on participation, it is essential to understand the content detailed in the informed consent template, what clinical research does and how it works.

Trust in the physician, and in the healthcare facility generally, can play a role in the decision to take part in a clinical study [12, 13] and the physician's willingness to maintain a relationship open to the individual's questions, doubts and preferences can foster it.

There is substantial literature on the concept of informed consent in clinical research, addressing its value, limits and significance, especially for clinical studies [14,15,16,17,18], including many templates [19, 20]. According to the literature, however, Informed consent forms are often unclear and poorly understood by participants [14, 16, 17].

There are plenty of informed consent forms, differing widely at international, national and local levels. Within the H2020 CORBEL project, comprising 37 institutions from 13 biological and medical sciences research infrastructures [21], persons with different areas of expertise collaborated to define an exhaustive set of requirements for informed consent, for adults in relation to clinical studies. The aim was to provide a common tool as a proposal to be used by researchers, taking advantage of the CORBEL consortium. The overall purpose was to address the issues of the many informed consent forms in use—i.e. wide variability, language and topics often poorly understood by participants—paying particular attention to the setting and the process of communication.

Methods

We decided the approach on the basis of our multidisciplinary backgrounds and expertise as clinical researchers and researchers in ethical, social, and legal issues, experts in planning and management of clinical studies, clinicians, researchers in citizen involvement and public engagement.

Literature review

We consulted the literature to define the characteristics and topics for an informed consent document that aimed at increasing the understanding and awareness of people interested in participating in a clinical study. The literature review included systematic reviews (SRs) on PubMed, Embase, Cochrane Library, and guidelines (GLs) on PubMed, Embase. The research question was: “What characteristics and what topics should an informed consent contain to increase the understanding of people interested in participating in a clinical study?”. The search was done in February 2017, and the search strategy is reported in Additional file 1. An additional search for relevant guidelines was done on NICE, SIGN, GIN, and clearinghouse databases in March 2017.

We included SRs of studies where the intervention was the informed consent form and/or process of information, the comparison was the standard informed consent form and/or process of information, and the primary outcome was understanding. We also considered the increase of participation in clinical studies and in the decision-making process as secondary outcomes. If these were primary outcomes, then the SRs were excluded. The screening was done independently by two reviewers (CC,SR). Discrepancies were solved by discussion. The SRs were appraised using the AMSTAR checklist [22].

Collection of informed consent templates

As a starting point, we decided to refer to informed consent templates already in use, making an overview of the topics and suggestions by template, comparing them and then discussing them among the authors. We gathered information sheets and informed consent templates available to and/or recommended by the authors’ group, as well as from an extensive web search on the websites of research institutes, national and international research and health agencies, ethics committees, international initiatives and projects (collected by the end of February 2017).

The persons in charge of this task (CC, PM) summarized the main topics and recommendations of each template and/or information sheet and identified a set of common topics and suggestions, adding further items according to the agreements reached among the authors, as reported below.

Revision of the draft

CC, PM drafted a first version of the CORBEL template and circulated it by email to the other authors. This version was then discussed in a face-to-face meeting, deciding on the main topics. We followed a step-by-step process of reiterative discussion on agreed and open points. Further versions were discussed by teleconference and e-mail. Main revisions were on the sequence of topics (e.g. on moving sections on secondary use of biosamples and data after main sections on the use of biosamples and data). In some instances, revisions concerned what information should be added (e.g. on modalities to exercise the data protection rights of clinical trial parcipants).

We finally agreed on an advanced version that was further revised by patient representatives of the European Patient Forum, and the European AIDS Treatment Group. The final version included their revisions on wording, content, and sequence of topics. For example, we modified the term “research subjects” with the term “participants”, we specified the meaning of “sponsor”, added information about the possibility of having individual feedback of findings and added details about the indirect burden of participating in a trial. The sequence of topics was modified to focus first on the process of information, and second on the main topics of the matrix, moving to general suggestions on wording, format and layout at the end.

Results

Literature review

We retrieved 339 SRs, excluded 299 by title and abstract, and 26 by full text, because they were identified as not pertinent (e.g. not dealing with informed consent; dealing with informed consent for surgery or medical interventions). Finally, we included 14 SRs on informed consent templates. Searching for related guidelines, we retrieved 116 items, excluded 108 by title and abstract, and 8 by full text. We excluded guidelines as the resources retrieved were authors’ comments or expert opinions that did not use systematic methods to search for evidence or criteria for selecting it, and did not link the recommendations to the evidence.

The list of SRs included and their results are reported in Table 1, with more details in Additional file 2. The methodological quality of most SRs was moderate or high according to the AMSTAR checklist.

Table 1 Systematic reviews included: main characteristics and findings

The findings indicate that many participants in clinical studies are neither fully aware that they are participating in a study, nor do they understand the experimental nature of these studies or the meaning of randomization. Many are convinced that they are receiving new treatment (also known as “therapeutic misconception”)—not knowing they could be taking the standard treatment or placebo—and they expect substantial benefit from the treatment (known as mis-estimation). Many do not know that they may be given a placebo and what "placebo” means [16, 23,24,25]. Legal information and a reference to positive ethical approval are among the most frequent details provided in the forms.

Suggestions from the literature refer to the process of communication and the informed consent template. These include providing simple information focused on the person’s information needs, according to reading and language ability; communicating with the person in proper space and time, leaving the person enough time to think about the proposal; creating conditions and a relationship where the person feels free to ask questions. Others are: summarizing and repeating the key messages related to participation in the study, and checking the person has understood by asking about any doubts or whether there are questions.

Some recommendations for informed consent templates are to write clearly and include short messages in a question-and-answer format, followed by explanatory details using different layouts and media and, if possible, providing links to additional material.

On the basis of the literature, we decided to focus on some items, such as non-inferiority trials, randomization, placebo, suggesting specific wording and citing a tool—the ECRAN animated film [26, 27]—illustrating these concepts in clinical trials. Additionally, we have drafted recommendations on the process of communication and the layout and wording (see Results section).

No strong indications or suggestions came from the included SRs on secondary outcomes. We discussed the findings during the development of the matrix, but refrained from incorporating topics or suggestions from the findings related to these secondary outcomes.

Overview and comparison of templates

We gathered templates from the European clinical research infrastructure network ECRIN, Health Research Authority (UK), Agency for Healthcare Research and Quality (UK), The Central Committee on Research Involving Human Subjects (CCMO) (Netherlands), the World Health Organization (WHO), the National Cancer Institute (USA), the Clinical Trials Transformation Initiative (CTTI), regional committees for medical and health research ethics in Norway (taken as suitable reference example). Table 2 compares the main characteristics of each template.

Table 2 Templates’ overview. Summary of the main characteristics of the patient information sheets

Suggestions were also taken from the ethical toolkit of the Italian National Research Council Commission on the Ethics of Research and Bioethics [28].

A minimum set of common items and suggestions deriving from the comparison are included in the final template reported in the Results section.

Consensus on the matrix

The literature findings and the overview of the templates were considered in a first draft in terms of structure, topics, layout and wording. We decided to refer to this as the “matrix” to underline that it has to be adapted to fit the specific legal, societal and research context in which it will be used. The final version is reported below with notes about the sources used.

Discussion

An informed consent form is often written in a formal, legalistic way that risks undermining the original aim [30], by reducing the processes of communication and decision-making to a signature [31]. Considering the ample attention paid to informed consent in clinical studies, and the mass of studies, it is time to put recommendations for multicentre interventional randomized clinical studies into practice and make the best of the resources available.

Considering the amount of studies in the EU Clinical Trials Register, which on 21 July 2020 comprised 37,606 clinical trials [32], the ethical duty to provide complete and correct information in informed consents is increasingly important and concerns a huge number of studies’ participants.

As extensively reported by literature, informed consent forms are often too long, not easy to read, and poorly understood by the research participants [14, 16, 17, 23,24,25].

A conversation with a health care professional—frequently limited by time and space constraints—is often the only basis leading to signed informed consent, and depends heavily on their individual communication skills. Often scant attention is paid to participants’ doubts and questions. Consequently, we underline in the Matrix the importance of improving the communication process and skills, the proper conditions (space, time, setting), the legal and social context, and the cultural environment, considering the lack of knowledge about how clinical research is conducted, and the desire to open up participatory research between health professionals, and citizens and patients. We also suggest tools for participants wanting to know more about the methods of clinical studies.

To reach a consensus on the matrix, we did not apply a standard qualitative methodology, but we used a step-by-step process of reiterative discussion on agreed and open points, first face-to-face and then by e-mail and teleconference.

The CORBEL matrix is designed to provide a useful tool, not only to help identify the most appropriate informed consent format for a specific study, but also to provide suggestions and recommendations on how to present and discuss information by drawing on the templates of organisations and projects that have dealt with clinical studies for years. The matrix enables modifications to take account of the variability of informed consent templates for clinical research so that it can be easily applied to a specific setting, including an ethics committee’s particular requirement.

During the development, attention was paid to strike a good balance between the amount and the clarity of information (incl. suggestions on wording) provided. Although it includes a wide range of information, the matrix allows adaptations also in terms of the length of the form, balancing information according to the type of study. Too often long, complex informed consent forms are presented to participants, not meeting their actual information requirements.

According to the frame of the project, grounded on literature findings and templates already available, we decided to involve patient representatives as reviewers of the matrix, so as to respond better to participants’ needs. We need to acknowledge, however, that including patient representatives from the very beginning would have likely permit a more meaningful level of participation and deepen co-production of results.

The matrix was intended to be applicable in different settings. It covers broad topics, and provides general suggestions. It does not address country-specific legal requirements and societal concerns. It was outside of our scope to assess the final matrix for clarity and user-friendliness.

Conclusion

The matrix was developed in the framework of the CORBEL consortium of research infrastructures [21]. It has been disseminated within the CORBEL network and is included in the BBMRI-ERIC ELSI Knowledge Base [33] to ensure its availability beyond the project’s lifespan. For wider application, it will be important to advertise,observe and possibly test the implementation of the matrix in real-world settings in research centres, by patient groups, and its translation and adaptation to national, if not regional contexts and electronic formats. Wider uptake has to be carefully monitored, in order to improve the matrix wherever necessary.

Under the right conditions, informed consent could be an important participatory tool if properly discussed by clinical researchers with potential study participants.

Ultimately, improving informed consent templates and procedures in clinical practice is essential because practice and research are two closely linked sides of the process of care.

Availability of data and materials

All data generated or analysed during this study are included in this published article [and its Additional files].

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Acknowledgements

The authors thank Kaisa Immonen, Director of Policy of the European Patient Forum, and Pedro Silvério Marques, European AIDS Treatment Group for their feedbacks and comments; Vanna Pistotti,Silvia Radrezza and Andrea Fittipaldo—Istituto di Ricerche Farmacologiche Mario Negri—for their collaboration in the literature review, and Judith Baggott for editing.

Funding

This project receives funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 654248. The funding body played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

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Contributions

CC, MTM, PM made substantial contributions to the design and development of the project, CC, MTM, CK, SB, MM, ML, SC, VC, IS, TC, PM made substantial contribution to the discussion and interpretation of findings. CC drafted the manuscript and MTM, CK, SB, MM, ML, SC, VC, IS, TC, PM substantially revised it. CC, MTM, CK, SB, MM, ML, SC, VC, IS, TC, PM approved the submitted version. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Cinzia Colombo.

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Supplementary Information

Additional file 1

. “Search strategies of the literature research”. Details of the search strategy by database.

Additional file 2

. “Systematic reviews included: main characteristics and findings”. Summaries of characteristics and relevant findings of each systematic review.

Additional file 3

. “Notes from the templates to define suggestions on wording, format and length in the Matrix”. Main suggestions on wording, layout and length from templates.

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Colombo, C., Mayrhofer, M.T., Kubiak, C. et al. The CORBEL matrix on informed consent in clinical studies: a multidisciplinary approach of Research Infrastructures Building Enduring Life-science Services. BMC Med Ethics 22, 95 (2021). https://doi.org/10.1186/s12910-021-00639-x

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Keywords

  • Informed consent
  • Clinical studies
  • Biomedical research
  • Consent template