The informed consent process is a principle in clinical research, important for safeguarding the patients' welfare, with ethical, legal, and practical implications.[1] The evolution of the informed consent begins with the Nuremberg code in 1947, which was developed in response to the unethical trials of Nazi doctors on human subjects and represents the first international document focusing on the voluntary consent of a participant in a research study.[2] In 1964, the Helsinki Declaration included a set of general ethical principles and standard guidelines for physicians engaged in medical research based on human subjects, including their material and data, as developed by the World Medical Association.[3] To protect human subjects of biomedical and behavioral research, the National Research Act (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research) was signed into law in 1974, developing guidelines based on ethical principles, which are summarized in the Belmont Report and should be followed to ensure that research on human subjects is conducted according to them.[4] In 1982, the World Health Organization and the Council for International Organizations of Medical Sciences created the International Ethical Guidelines for Research Involving Human Subjects to improve and complement the implementation of the Declaration of Helsinki.[5] It included laws and regulations for the participation of human subjects in research, standard principles for research procedures, and the adequate and voluntary participation of each subject. In 1996, the International Guideline for Good Clinical Practice was developed, to create international harmonized standards implemented in clinical trials.[6] Most recently under European law, established in 2016 and taking effect in 2018, the General Data Protection Regulation (GDPR)[7] was formulated and governs all the processing of collection, storage, and sharing of personal data associated with participants. GDPR sets an international guide applied to businesses and organizations, as well as the lawful basis for individuals' rights, including informed consent guidance.
In practice the informed consent provides meaningful information to potential participants, including all aspects of data disclosure, to help them fully understand the research program they are going to be involved in and empower their autonomous decision-making.[8] It is a legal and symbolic agreement between patients and healthcare or research stakeholders, considered complete and valid if the following four major criteria are fulfilled: information disclosure, competence, comprehension, and voluntariness, taking into account patients' differential capacities.[9]
CURRENT PRACTICE OF INFORMED CONSENT
The current process of informed consent is based on formal educational sessions, in which relative information shall be provided to each participant before a research plan begins, leading to their voluntary decision to participate.[10] This process includes: purpose and description of the clinical or research investigation; possible risks and discomforts to the subject; potential benefits; total duration; all the experimental procedures; any available compensation and medical treatment in a possible event of injury; the subjects' right to confidentiality and right to withdraw; whom to contact for future questions and other alternative options for treatment; information about their data disclosure; information affecting their personal privacy, as well as their future relationship with the involved entities.[11,12] Currently several types of consent are introduced in research to obtain participants' engagement for biosample donation, including the following[13–17]:
Blanket and broad consent: participants donate their samples for a broad spectrum of future studies without any restrictions or specific limitations.
Study-specific consent: participants donate their biosamples only for a specific research type.
Tiered consent: participants can partly tailor their consent preferences, but only for specific study types.
Meta consent: participants are enabled to choose their consent options for specific categories of data within different types of research tiers.
Dynamic consent: participants are enrolled in their consent status monitoring and modification associated with research activities of biobanks and other entities.
For the purpose of a sufficient recruitment of patients to clinical research, a face-to-face informed consent can present considerable barriers and difficulties in its implementation, such as the adequate training of consenting staff and the travel burden[18] to name two; this method affects costs and time frames of clinical research studies, in some cases leading to ultimate failure.[19] As part of clinical research and the development of personalized medicine, an increased number of research infrastructures are being built to collect, process, and store great amounts of human biospecimens for future analysis.[20] Thus, scaling up and monitoring the informed consent process becomes challenging. In addition, the communication among stakeholders to provide a unified, effective coordination of healthcare processes in response to those increased pressures becomes increasingly complicated especially when the multitude of different electronic systems embedded within healthcare operations is considered.[21] This leads to the need for development of innovative digital tools for data exchange and new technologies for informed consent.
For a unified and harmonized approach on the issues of informed consent, electronic mechanisms have been introduced, as novel digital processes of engagement, with a view to replacing and improving the traditional paper-signing methods.[22] The e-consent includes multimedia components and provides numerous forms of interactions and customized options for the voluntary participation of a subject in a research study.[23] It is the process not only of obtaining a signature from the subject, but also of developing an interactive procedure that provides adequate information and increases participants' comprehension, by using multiple electronic systems and processes, such as text, graphs, audio, video, podcasts, websites, biological devices, and card readers, as shown in Figure 1.[24]
ELECTRONIC INFORMED CONSENT (E-CONSENT)
The e-consent processes incorporate all the regulatory requirements and key elements recommended for cybersecurity, ethics, privacy, and data protection associated with patients' identity and personal data, as well as create real-time enrolment, which enables easier patient recruitment.[25] The e-consent tool also overcomes the aforementioned challenges limiting the numbers of recruited participants. It provides the foundation for scaling up clinical data analyses for a large number of diseases, an aspect that is considered especially important in the case of rare diseases research. With e-consent, specific patient target groups can be easily informed, educated, and incorporated into subsequent-generation projects, offering a novel tool for research communication, collection, process, storage, and analysis of disease-specific data sets.[26] The effectiveness of international large-scale cohort studies for long-term follow-up, with the use of e-consent, is increased and the cost and time for patients' recruitment are reduced.[27] During the coronavirus disease 2019 (COVID-19) pandemic, research infrastructures based on the e-consent model have been established, to create innovative tools for clinical care and recovery, setting the basis for the new era of real-time patients' engagement process.[28,29]
In addition, e-consent enables the redistribution and searchability of data, via participants' designation for data aggregation and usage for future analysis.[30] The availability of open-data sharing with many researchers simultaneously, as an option of the e-consent procedure, can maximize the scientific value of the patients' data and improve the management of health research. This innovative interactive consent experience contributes to the personalized consent form creation, considering the preferences, needs, learning style, and ability of each individual.[31] Through the use of a real-time, interactive, multimedia environment for consent process, there can be significant impact on both participation and organization of studies, as it can be implemented on platforms for international patients' real-time data records.[32]
Although e-consent has many benefits, a number of challenges should be taken into account for a successful design, including factors such as accessibility, presentiveness, validation, privacy, patients' verification, authentication, technical support, consensus among the stakeholders, comprehension, data security, and compliance.[33–35] These challenges become even more complex when considering the scale of e-consent implementation required for biobanks for the storage of biospecimens and data, for longitudinal studies, in particular the large number of individuals and associated data from multiple sources that would be linked to these specimens.[36,37] For the successful international collaboration between healthcare research entities, harmonization and interoperability remain essential parameters, including the consent process. Hence, validated standards and innovative technology should be established, addressing the different types of regulatory mechanisms, applied in different countries, and the lack of common ontology systems that might result in data loss and bias.[38–41]
DYNAMIC REAL-TIME E-CONSENT: A NOVEL TOOL
To improve both patients' experiences and healthcare research needs (Table 1), Metabio,[42] a biotechnology startup creating novel information technology (IT) solutions targeting the biobanking and all related industries, designed an innovative system, an implementable dynamic real-time e-consent incorporating multiple functionalities, for the management of medical data and specimens. This dynamic real-time (DRT) e-consent provides an evolution of patients' engagement in research and the ability to obtain real-time longitudinal data, including clinical secondary data.
The system is based on provisions and expanded functionalities on the digital rights management (DRM) technologies,[43] used for data storage, processing, and sharing, which enable the development of novel collective intelligence methodologies. The digital rights management system has a digital rights management machine that includes a method of authorizing access to electronic content. The method of access authorization to and/or use of electronic content (medical records/data) for use in a digital rights management system includes an electronic digital rights management system. In the electronic management system, the donor/patient alters in real time the consent status for the storage, preservation, and use of the human specimens and medical data as identifiable, anonymized, identified, or coded. Assignment, change, or withdrawal of electronic consent and/or authorization to use digital data and natural specimens by a donor/patient determines the electronic management of data, the type and field of research, the time of retention of data, samples or medical records (individual or collective), and the communication of different users with the subject. The method includes the electronic definition of the use or access per user in the chain of use of the electronic content and alters the permission to use, the possibilities of communication of the parties in the chain of use, and the creation of bidirectional communications. Recognition of permission through consent includes the control program, according to the request for determining the use or access, that is, that the requested access or other use of the electronic content is allowed.
The e-consent tool enables the multiple searching and user setting through only one system and connects data from different demographic areas in one multidimensional environment for data flow. The registered and authorized users are permitted to use common mechanisms and privacy tools, to submit queries, and to analyze multiple data sets.
The dynamic e-consent provides a monitoring tool for patients' engagement, by informing all the entities for change in the consent status in real time. It also keeps subjects more deeply engaged for clinical research retention, by providing them with more details on research information and making the consent process more understandable and interactive.
The e-consent system operates under GDPR and HIPAA (Health Insurance Portability and Accountability Act) compliance, following all the layering for cybersecurity, data privacy, integrity, and disclosure and providing increased efficacy, data quality, accountability, and transparency. The security infrastructure is specifically designed and supported by fast fully homomorphic encryption techniques (FFHE),[44,45] so as to achieve adequate protection and security for all data and users.
By deploying dynamic real-time e-consent, patients are fully informed and enrolled in a consent status management, with the privilege to configure the use chain of specimens and data, by determining both the context of use and the rights of all users in the deployment of electronic system within a network of entities. The tool ensures that patients can exercise control over their health data and are included in healthcare management and decision-making. Moreover, it improves patients' comprehension and enables them to create a personalized interface.
In conclusion, in the era of data analytics and high-throughput technologies used in research, and considering the vast amount of data already linked to human specimens, the implementation of dynamic e-consent tools can improve the consent process and transparent accessibility to relevant clinical information. It is critical to continue improving and updating the consenting processes for greater patient engagement and the democratization of clinical research and information.
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