Ethical Considerations in Informed Consent

Abstract

The process of informed consent, a fundamental aspect of clinical research, involves providing research participants with information about a study and obtaining their voluntary agreement to participate. Its purpose is to safeguard the rights and welfare of participants by ensuring that they comprehend the nature, potential benefits, and potential risks of the research and can make an autonomous and informed decision about whether to participate. The history of informed consent in clinical research is relatively recent, beginning with the Nuremberg Code in 1947 and evolving through subsequent codes and laws such as the Declaration of Helsinki, the Belmont Report, the CIOMS guidelines, and the US Common Rule. There is a general ethical agreement on the structure and information that should be included in informed consent in order to ensure that participants have all the necessary information to make an informed decision. This chapter aims to provide an overview of significant historical milestones in the development of informed consent, current consensus on its structural features, and examples of situations where obtaining informed consent may pose a challenge, such as cluster-randomized clinical trials or decentralized clinical trials.

1. Introduction

Informed consent is a process in which a participant in any clinical investigation is informed about the details of the study and any potential risks and benefits. It is an ethical and legal requirement for any research involving human participants [1]. Although it may seem that informed consent has always been there in time as a critical ward of patient’s right to autonomy, the truth is that the concept of informed consent has a relatively short history [2]. The Nuremberg Code [3], developed after World War II in response to the Nazi medical experiments, established for the first time the principle that informed consent is essential for ethical medical research. The Code, issued in 1947, drafted some central ethical unquestioned principles that were reinforced afterward in subsequent declarations and laws, such as the principle of autonomy, which was brilliantly crystalized at the first statement of the Code:

“The voluntary consent of the human subject is essential. This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, overreaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision.”

This first section clearly describes one of the fundamental ethical principles in clinical research that would later be called the principle of autonomy or respect for persons. For the first time, it was made clear that a subject’s participation in clinical research is voluntary, and that the decision to participate or not should be made free of coercion or fraud. It also describes that the subject must have sufficient information about the characteristics of the study, its possible benefits and risks, to be able to make an informed decision about their participation. In this regard, without explicitly naming it, the first statement of the Code clearly highlights the importance of the concept of informed consent, as a critical safeguard of this fundamental principle.

In 1964, the first version of the Declaration of Helsinki, issued by the World Medical Association [4], further developed the process of informed consent and its ethical implications. It first described that the responsibility of explaining the study to the subject falls on the investigator or clinical doctor: “The nature, the purpose and the risk of clinical research must be explained to the subject by the doctor.” It also states, in line with the Code, that “Clinical research on a human being cannot be undertaken without his free consent after he has been informed; if he is legally incompetent, the consent of the legal guardian should be procured.” The Code had introduced the concept that the subject must be “legally capable” to consent autonomously, but the Declaration expands this principle by allowing a “legal guardian” to consent. Section 3c of the Declaration states that “Consent should, as a rule, be obtained in writing,” envisaging the need to reinforce the informed consent process with a written support (the informed consent form). Finally, the first version of the Declaration extends the autonomy principle not only to participate in any kind of clinical research, but also to the withdrawal of such participation, as stated in Section 4b: “At any time during the course of clinical research the subject or his guardian should be free to withdraw permission for research to be continued.”

The Declaration were revised and updated at subsequent meetings in 1975, 1983, 1989, 2000, 2008, and 2013, but the statements regarding informed consent have been essentially unaltered since the inception of the first version back in 1964.

It is important to note that none of these ethical statements mentioned above, although widely accepted worldwide, were legally binding. In this regard, in 1974, The National Research Act, a United States federal law, established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. This commission was created in response to concerns about the ethical conduct of research involving human subjects, especially the Tuskegee syphilis study, in which African American men were not informed of their diagnosis or treatment and were left untreated even after penicillin became available as a cure [5].

The Act gave the commission the authority to study and make recommendations on the ethical principles involved in biomedical research, regarding the protection of human subjects. The Commission also developed guidelines for the conduct of such research, crystalized in the Belmont Report in 1979 [6]. The Belmont Report is considered a seminal document in the field of research ethics. The report first establishes in a formal manner the three basic ethical principles that are considered particularly relevant to the ethics involving human subjects: respect of persons (or autonomy), beneficence, and justice. Once again, the ethical principle in which the process of informed consent lies is highlighted, but with special attention to what “autonomy” means regarding participation in a clinical investigation. As it is stated in the Report:

“In most cases of research involving human subjects, respect for persons demands that subjects enter the research voluntarily and with adequate information. In some situations, however, application of the principle is not obvious. The involvement of prisoners as subjects of research provides an instructive example. On the one hand, it would seem that the principle of respect for persons requires that prisoners not be deprived of the opportunity to volunteer for the research. On the other hand, under prison conditions they may be subtly coerced or unduly influenced to engage in research activities for which they would not otherwise volunteer. Respect for persons would then dictate that prisoners be protected. Whether to allow prisoners to ‘volunteer’ or to ‘protect’ them presents a dilemma. Respecting persons, in most hard cases, is often a matter of balancing competing claims urged by the principle of respect itself.”

This paragraph examines the nuances of the principle of autonomy in research. Using the example of the prison population, it illustrates how various forms of subtle coercion or inducement can significantly undermine this principal. Additionally, the inherent power imbalances between different groups of individuals can pose challenges to preserving autonomy, particularly in hierarchical relationships such as employer-employee or patient-physician relationships. It is crucial to implement measures to ensure that autonomy is upheld to the greatest extent possible for a subject’s participation to be valid in a clinical investigation.

The Belmont Report is also the first internationally accepted ethical code to outline the general structure and information that must be provided in the informed consent. It posits that informed consent comprises three key elements: information, comprehension, and voluntariness. Regarding the information element, the report stipulates that informed consent should generally include details about the research procedures to be employed, the rationale for conducting the research, the potential risks and benefits associated with participation, alternative options for treatment or care, an opportunity for the individual to ask questions and also to withdraw from the research at any time, and information about the participation selection process and the roles and responsibilities of the researchers involved.

The report emphasizes, regarding the comprehension element, that the way information is presented and the context in which it is conveyed are as crucial as the information itself. For example, presenting information in a disorganized or rushed manner, or not providing sufficient time for individuals to consider the information, can negatively impact their ability to make an informed decision.

Finally, the report once again highlights the importance of guaranteeing the voluntary nature of the entire informed consent process, delving into the fine line that separates coercion of undue influence.

It should be noted that the National Research Act of 1974 is not legally binding (nor the Belmont Report), but it established the framework for federal regulations for the protection of human subjects in research, which was implemented later by the U.S. Department of Health and Human Services with the Federal Policy for the Protection of Human Subjects, also known as the “Common Rule” in 1991 [7]. In this regard, during the 1990s and 2000s, many countries began to adopt and pass specific regulations regarding the participation of human subjects in biomedical research, highlighting the importance and obligation of obtaining the voluntary informed consent of study participants before enrolling them in a clinical investigation. As an example, informed consent for research was made legally binding in the European Union with the adoption of the European Union’s Clinical Trials Directive 2001/20/EC, which was implemented in 2004 [8], in France in 2004, with the passing of the law No. 2004–800 [9], and in Japan in 2003 [10].

In 1982, the World Health Organization (WHO) and the Council for International Organizations of Medical Sciences (CIOMS) issued the International Ethical Guidelines for Biomedical Research Involving Human Subjects, also known as the WHO-CIOMS Guidelines [11]. These guidelines provide a framework for the ethical conduct of biomedical research involving human subjects, including the requirement for informed consent, and they detail on how these universal ethical principles should be applied. So, the guidelines state and remark that obtaining an informed consent is a fundamental principle in biomedical research and that it is essential to respect the autonomy of the research participant. An informed consent, as specified in the guidelines, is required for all research participants and that the informed consent process must ensure the individual understanding of the nature of the research and the potential risks and benefits involved. Also, the language of the information provided to participant must be one that they understand that sufficient time should be given to a participant to consider participating, and that the participants have the right to withdraw at any time without penalty. Furthermore, if the participant is incapable of giving informed consent or is not legally competent or is underage, the guidelines require that investigators must obtain it from the legally authorized representative of the participant or from the parents or legal guardians of a child, or the legal guardian of an adult incapacitated person when a child or incapacitated person is the research subject. Overall, the WHO-CIOMS guidelines once again emphasize the importance of an informed consent as a fundamental principle in biomedical research involving human subjects, ensuring participants rights and autonomy, and providing a framework for the ethical conduct.

The WHO-CIOMS Guidelines were revised in 1993, 2002, and 2016. These guidelines have been conceived to facilitate the practical implementation of the subsequent versions of the Declaration of Helsinki in all WHO member states, including low- and middle-income countries. The 2016 version [12] include an appendix (Appendix 2), in which it details the essential information to be included in the informed consent form for prospective research participants.

In conclusion, informed consent is an ethical and legal requirement for any research involving human participants. The concept of informed consent has a relatively short history but has become a fundamental principle in clinical research. The Nuremberg Code, developed after World War II in response to Nazi medical experiments, established for the first time the principle that informed consent is essential for ethical medical research. The Code and subsequent declarations, such as the Declaration of Helsinki, have reinforced the importance of informed consent as a critical safeguard of the principle of autonomy or respect for persons. The Declaration of Helsinki has been revised and updated over the years, but the statements regarding informed consent have remained largely unchanged. It is important to note that the principle of informed consent is continuously evolving with new laws and regulations, but the basic principle has been unaltered since inception, to ensure the autonomy and protection of human subjects in research.

2. Informed consent process and structure of an informed consent form

As previously commented, biomedical research carried out on human subjects must comply with current ethical and legal principles that guarantee individual autonomy to either accept or reject their participation. Therefore, informed consent acts as a safeguard that should adequately provide relevant information from scientific research, granting the freedom to consider their involvement and not be coerced to participate in the study.

In obtaining and documenting informed consent, the researcher must comply with ethical principles, current legislation, and good clinical practice standards, highlighting that the informed consent document or form has a central role during this process [13, 14]. The researcher needs clearly explain the details of the study, providing the opportunity and sufficient time to the subject or his legal representative to ask or inquire about the study and answer satisfactorily, so the subject gets the correct information and afterward has enough time to decide whether to participate in the study [15]. Overall, the informed consent is a two-way communicative process.

The WHO-CIOMS guidelines, as mentioned in the introduction of this chapter, contain 26 items that must be met before seeking a person’s consent to participate in a research study. These items detail the information the researcher must adequately communicate to each participant and that it must be reflected in the informed consent form [12].

During the process of obtaining the informed consent, the researcher must initially inform the participant; consequently, it must be stated in the informed consent form or document that they are being invited to participate in the research, that their participation is voluntary, explain the reasons for their eligibility as a participant, and that they are free to refuse participation and withdraw at any time without penalty or loss of benefits. In addition, on the informed consent form, the current regulations must be explicitly cited.

On the informed consent form, and during the process of obtaining the informed consent, participants must be informed about the sponsor, the sources of research funding, and the research ethics committee and regulatory entities involved in the evaluation, approval, and authorization of the research protocol.

Subsequently, the purpose of the investigation, its methods, the procedures that the investigator and the participant will carry out, and an explanation of the difference between the investigation and routine medical care must be explained. The expected duration of the participation and the possibility of an earlier termination than stipulated must be informed. After the end of the study, the participants will be informed of the results of the research in general, if they so wish. Each participant will also be provided with potentially lifesaving and immediately clinically useful information about a major health problem. In addition, they will be informed of their right to request their clinically relevant data, unless the data have been temporarily or permanently approved not to be disclosed, in which case the participant should be informed of that decision and explained the reasons.

The inconvenience and risks derived from the study must be reported, taking into account whether or not the interventions or treatments carried out have authorization from the different regulatory agencies and the previous experience available; potential clinical benefits, if any, that could result to participants or society in general and contributions to scientific knowledge; currently available alternative intervention or treatment; and any new information that may have come to light, either from the study itself or from other sources, will be reported.

In case of possible violations of the protocol, these will be informed, in addition to the necessary information to guarantee the safety and well-being of the participants in these cases.

It should also be reported how the transition to postinvestigation care is organized and to what extent participants will be able to receive beneficial interventions postinvestigation and will have to pay for them.

Concerning confidentiality, the measures that will be taken to ensure the privacy of the participants, the records in which they are identified, the ability of researchers to protect the confidentiality, and the possible consequences of violations of this provision must be reported.

Regarding the researchers, their institutional affiliation, as well as their degree of responsibility to attend to the health needs of the participants during and after the research, should be reflected.

In addition, it must be reported in case of having it, the contracting of a study insurance policy, the name of the medical service or the organization that will provide the treatment, explaining that treatment and rehabilitation will be given free of charge for specified types of damages related to research or complications associated with it, the nature and duration of such care, and whether there is any uncertainty regarding its financing.

In the case of providing financial compensation for participation in the research, the type and amount must be specified, considering the time dedicated to the investigation and other inconveniences resulting from the participation in the investigation and that these are duly compensated, following the current legislation of the country if it allows it.

Furthermore, an informed consent document must be written at an appropriate reading level for its audience and be long enough to allow full and thorough reading of the information and study details, which may help the participant decide.

2.1 Specific cases

If there are specific characteristics in the design, said information must also be provided in a language or other form of communication that the participant can understand correctly, avoiding technicalities.

The WHO-CIOMS guidelines also stipulate that the participant must be informed in case of presentation.

In the case of controlled studies, an explanation of features of the research design (e.g., randomization and double blinding) should be included, using less technical language alternatives. The participant must be informed that the assigned treatment will not be communicated until the study has been completed and the blind has been broken, except for some circumstances that may affect the safety of the participant or the investigation. In addition, the participants must receive all essential information; otherwise, they must be informed about it and request their acceptance to receive incomplete information, clarifying that, before study results are analyzed, the participants will receive all the information and will have the possibility to withdraw their data collected under the study.

In case of the use of genetic test results and family genetic information, the participant must also be informed, as well as the related legislation and the precautions taken to avoid the disclosure of the genetic test results of the participant to close relatives, friends, or other people without your consent; In addition, if the possible uses of medical records and biological samples taken during clinical care are stipulated.

When the collection, storage, and use of biological materials and data related to health are carried out, it must be reported following what is described in the CIOMS guidelines, in addition to considering the current legislative regulations associated with each country.

The specific informed consent to collect biological samples must contain detailed information that may include storage regime, conditions and duration of storage (where, how, for how long and final disposition), foreseeable uses including its possible future use, if intended for research only or also for commercial purposes, measures taken to protect confidentiality, and the participants right to decide on such use, refuse storage, and demand that the material be destroyed (CIOMS 2016).

If the research involves women of childbearing age, information must be provided as described in CIOMS guidelines 18 and 19 and Appendix 2, informing about the possible risks if they become pregnant during the research, risks to themselves (including the future fertility), their pregnancies, their fetuses and their future offspring, and guaranteed access to a pregnancy test, effective contraception, and safe and legal abortion before being exposed to a potentially teratogenic or mutagenic intervention. When effective contraceptive methods or safe abortion practices are not available and testing at alternative sites is not feasible, women should receive information about: risk of unintended pregnancy; legal grounds for undergoing an abortion; harm reduction from unsafe abortion and subsequent complications; and, when the pregnancy is not terminated, assurance of medical follow-up of their own health and that of the infant and child, and information on the frequent difficulty in determining causality in cases of fetal or infant abnormalities. When it comes to women during pregnancy and lactation, the risks of participating in health-related research to themselves, their pregnancies, their fetuses, and their future offspring, which has been done to maximize potential individual benefits and minimize the risks, that the evidence about the risks may not be known or controversial, and that it is often difficult to determine causality in cases of fetal or infant anomalies are best described in CIOMS guidelines 4 and 19.

Another situation to consider when obtaining and documenting informed consent is the use of online or digital tools in which potentially vulnerable people could participate; therefore, sufficient information about privacy and security controls that will be used to protect your data must be provided, as well as the limitations of the measures used and the risks that may persist despite the established protection measures.

3. Scenarios where obtaining an informed consent can be especially challenging

As mentioned previously, during the process of obtaining an informed consent, the investigator needs to ensure that the research participant has understood what the participation means to make an informed decision. Usually, this is done in a face-to-face interview where the research participant decides voluntarily to participate in writing by signing the informed consent form [16]. But there can be situations or scenarios where obtaining an informed consent can be especially challenging or even not required. For example, some situations include cluster clinical trials (CRTs) and decentralized clinical trials (DCTs).

3.1 Cluster clinical trials

CRTs are defined as clinical trials in which intact groups, units, or clusters of people, rather than individuals, are randomized to study arms or interventions and the outcomes are measured on individual cluster members [17, 18].

CRTs are commonly used for the evaluation of public health, health system, and knowledge translation interventions delivered at the cluster level [18]. The clusters most used may include medical practices, hospital wards, nursing homes, schools, and communities [17]. Also, CRTs may be useful for the evaluation of individual-level interventions when the use of individual randomization may not be practical. For example, a CRT with the aim for reducing infection rates in intensive care units or in operating rooms by means of educational intervention on healthcare professionals on a new hand-washing technique to help avoid transmitting infection that randomizes intensive care units or operating rooms, intervene upon healthcare professionals, and measure outcomes on patients [17, 18, 19]. Another example can be the evaluation or indirect effects of vaccines in trials of vaccination or intravenous fluid resuscitation protocol may be logistically easier to deliver to patients using cluster randomization [18].

Given that CRTs are complex and multilevel studies, they pose ethical issues to researchers, research ethics committees, regulators, and sponsors regarding the informed consent [18, 20].

A CRT may randomize hospitals or wards, but intervene on physicians, and collect data form patients, so this may give rise to different ethical questions: Who is the research subject? Who is entitled to ethical protections? From whom, how and when must an informed consent be obtained? Should an informed consent be sought for each patient or a representative of the hospital ward? [18, 20]. Being so, a key consideration when submitting a protocol to a research ethics committee is identifying the human research participants in the trial. These ethical questions are not present in individually randomized trials since most of the ethical guidelines regarding informed consent have been redacted for individually randomized clinical trials. Therefore, as a result from the lack of adequate guidance, the interpretations as to what are permissible ethical practices in CRTs are different within and across countries.

There are some guidelines published that were created in the intend to provide researchers and research ethics committees some practical guidance, some examples are the CIOMS-WHO guideline, the Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials, and the United Kingdom Medical Research Council Cluster Randomized Trials: Methodological and Ethical Considerations [12, 19, 21]. The Ottawa Statement includes 15 recommendations that attempt to give answer to the ethical questions raised by the design of CRTs. The statement gives a three-step framework to determine whether informed consent should be obtained from an individual or not. This three-step framework for navigating ethical issues of informed consent includes question-based steps: 1. Who are the research participants? 2. To what study element(s) are hey exposed? 3. For each study element, is a waiver of consent appropriate? [18]. Depending on the trial’s design, key lessons are provided. According to these key lessons, a difference should be made about informed consents. An informed consent for the study intervention and data collection should be separable and should correspond to the participant’s involvement in the study. The statements specifies that if consent is sought as soon as possible and prior to exposure to study interventions or data collection procedures, informed consent is not required for randomizations [18]. A useful practical tip is to get consent where you can. As a general rule, the CIOMS-WHO guideline establishes that an informed consent must be obtained from participants unless a waiver or modification of consent is granted by a research ethics committee [12].

In a cluster-level intervention trial that is delivered to the community, hospital, or social group as a whole and the cluster member cannot avoid exposure to the intervention, the Ottawa Statement says that the refusal of consent is effectively meaningless. The CIOMS-WHO guideline also establishes that in this type of trial, it may be virtually impossible to obtain individual informed consent. A classic example is a study comparing the methods of fluoridating the drinking water supply in a community to prevent dental carries [12]. Waiver of consent for any cluster-level intervention may be appropriate provided that the intervention poses only minimal risk to the participants. In this regard, historically, the waiver of consent was originally requested by researchers for observational retrospective studies, where a review of the medical records may only pose a low risk to the participants given that an adequate confidentiality protection system was in place. For example, The Common Rule establishes that the exempt research requires a Committee Ethics review to ensure that there are adequate privacy safeguards for identifiable private information and identifiable biospecimens [7]. Therefore, a research ethics committee needs to approve a consent procedure, which does not include, or which alters, some or all the elements of informed consent or waive the requirements to obtain informed consent. The research ethics committee must find and document that: (a) the research involves no more than minimal risk to the subjects; (b) the waiver or modification will not adversely affect the subjects’ rights and welfare; (c) the research could not be carried out without the waiver or modification; and (d) whenever appropriate, the subjects will be provided additional relevant information after participation in order to grant a waiver. In the context of CRTs, a low-risk category may be public health or educational practices.

In healthcare professional-level interventions, the question of who the research participant is must be answered to either ask for a consent or a waiver. When indeed they are the research participants, their informed consent should be obtained, unless the conditions of a waiver of consent are met. An example may be studies in which the intervention is delivered to a group team as a whole and the intervention cannot be divided among individual healthcare professionals [18].

Individual-level interventions and individually randomized trials mainly evaluate the same kinds of interventions that are delivered to patients and healthy volunteers; therefore, the considerations of informed consent are similar. For instance, if a waiver was not granted or not qualified for an individually randomized trial with the same characteristics of an individual-level intervention CRT, the intervention should not receive a waiver of consent in a CRT. If consent would be sought for an intervention in daily clinical practice, as for a drug or vaccine, a waiver of consent is never appropriate for that intervention in a CRT [18].

There is no real international consensus on to what the accepted justifications for informed consent waivers for CRT, but ethics research committees try to establish criteria to accept waivers that do not undermine the autonomy right of participants, that the participant is not exposed to a greater risk, and that the study may not be feasible without the waiver and is of an important social relevance. Also, it must be taken in mind the fact that individual choice to participate may not exist in a cluster intervention; it does not, for instance, prevent individual consent to complementary interventions as for example taking biological samples, recording information, or extracting data from health records.

3.2 Decentralized clinical trials

DCTs are clinical trials characterized by less dependence on research facilities or specialist intermediaries for data collection, in which the need for patients to physically access hospital-based sites is reduced or in some instances eliminated [22, 23]. DCTs take advantage of digital technologies and other methods or tools such as telemedicine platforms, sensory technologies, wearable medical devices, home visits, virtual patient-driven healthcare interfaces, and direct delivery of investigational study medications and materials to the homes of the patients to enable access, monitoring, and communication between researchers and participants [22, 23]. DCTs no longer require that patients frequently travel to healthcare facilities to participate in a trial and, thus, can adapt to patient’s routines and allowing participation regardless of the patient’s geographical position [22]. The disruption of the COVID-19 pandemic highlighted the importance and usefulness of digital technologies and decentralized procedures in a healthcare setting but also in some clinical trials [22, 24, 25]. Some clinical trials have already adopted many decentralized elements such as phone calls, online visits, wearables, and electronic diaries. How these decentralized elements are utilized will depend on the type of clinical trial, characteristics of the trial population, including diseases and physical condition (e.g., neuromuscular diseases), the type of medicinal product, and its development stage [24]. DCTs may be more suitable for conditions different from complex studies and for studies that are not excessively long. Ethic research committees must confirm that the use of these elements is appropriate as long as the rights, safety, dignity, and well-being of the participants is protected and prevail over all other interests, including the informed consent process.

While DCTs may provide some advantages to patients and trial sponsors, as mentioned previously, an important ethical aspect of a clinical trial is the informed consent. To give consent, participants need to be adequately informed about the trial, have opportunity to inquire about details of the trial, and have good communication with the investigator.

As has been discussed throughout the entire chapter, to properly inform a participant, a face-to-face interview with the researcher and potential participant needs to take place to ensure the willingness to participate, enhance mutual trust, and promote trial compliance [16, 24]. Thus, given the nature of DCTs that may involve an informed consent process in a remote manner and/or electronic methods for the signature of the informed consent form, several ethical aspects must be assessed including the trials design, its population, the risks, burdens, and potential benefits.

If only a part or the whole informed consent process is conducted remotely, the procedure needs to be described in the protocol of the trial, and a rationale behind using a remote approach must be detailed to the research ethics committee to ensure appropriate review. The recent recommendation paper on decentralized elements in clinical trials made by the European Commission and the European Medicines Agency states that the process should still be carried out in compliance with the principles laid down in the current clinical trial regulation or the directive, the ICH Guideline for good clinical practice E6 (ICH E6), the General Data Protection Regulation (GDPR), and national legislation.

The ICH E6 requires that all potential trial participants are fully informed on the clinical trial and provides the participants ample time and opportunity to ask questions and to decide whether to participate or not. All questions about the trial should be answered to the satisfaction of the potential participant [26].

The recent recommendation paper also states that, in the process of obtaining informed consent, it is considered essential that a face-to-face interview takes place between the potential trial participant and the investigator. If this communication is done in a virtual meeting, it recommends that this takes place in real time where both parties can see and communicate via audio and video. This remote virtual contact should allow the participant to ask questions, and the investigator should make every effort to check the identity of the participant if they are not already known by them, and conversely, the participant should have the right to ask for the proof of the investigator’s identity if they have not been in contact before [22]. Since a trial participant may hesitate to participate in a DCT, trial participants and investigators should be given the option to have the informed consent interview on site if this is preferred.

While the process of a face-to-face remote meeting to inform the participants may be ethically acceptable if all the requirements are met, the signature of the informed consent form rises legal issues. There may be ways in obtaining the signed informed consent form by remote means. These may include, for example, that the consent form is sent to the home of the participant for them to sign, and then, they send it back by post, or a digital consent form signed with an authorized electronic signature. Regardless of the format of the informed consent, the method should allow the reconstruction of the process, including the validity of the signatures. The Guidance for Industry, Investigators and Institutional Review Boards Conduct of Clinical Trials of Medicinal Products during the COVID-19 Public Health Emergency made by the U.S. Food and Drug Administration during the COVID-19 pandemic for decentralized activities in clinical trials that can be extrapolated to DCTs and the recommendation paper on decentralized elements in Europe both state that a method needs to be in place to ensure that the signer of the consent form is the person who plans to enroll as a participant in the trial and that the systems used have proportionate security levels and that safeguards regarding confidentiality are in place [24, 27].

Still DCTs need adequate guidelines, recommendations, and regulatory frameworks in order to favor harmonizations of both DCT ethical review and authorization of remote procedures and foster implementations of these trials.

4. Conclusion

The concept of informed consent arises from the basic ethical principle of respect of persons aka the patients’ autonomy and basic human rights. Regrettably, history has taught us that an informed consent is not only ethically correct but essential for conducting medical research and clinical trials. As established by ethical considerations and regulatory frameworks in research, an informed consent must respect the persons choice to participate or not in a clinical investigation. But this opportunity to choose is provided when adequate standards or requirements for an informed consent are satisfied, being a proper informed consent form that structurally is sound in giving all the necessary information to the participant and a face-to-face interview with the researcher and potential participant. This interview needs to take place to ensure the willingness to participate, given the opportunity to inquire about details about the research, and it may enhance mutual trust and promote trial compliance. There may be exceptions or situations in which the informed consent may be challenging or not even obtained, as are cluster clinical trials and decentralized trials.

Conflict of interest

The authors declare no conflict of interest.