Informing a European guidance framework on electronic informed consent in clinical research: a qualitative study.

BACKGROUND: Electronic informed consent (eIC) may offer various advantages compared to paper-based informed consent. However, the regulatory and legal landscape related to eIC provides a diffuse image. By drawing from the perspectives of key stakeholders in the field, this study aims to inform the creation of a European guidance framework on eIC in clinical research. METHODS: Focus group discussions and semi-structured interviews were conducted with 20 participants from six stakeholder groups. The stakeholder groups included representatives of ethics committees, data infrastructure organizations, patient organizations, and the pharmaceutical industry as well as investigators and regulators. All were involved in or knowledgeable about clinical research and were active in one of the European Union Member States or at a pan-European or global level. The framework method was used for data analysis. RESULTS: Stakeholders underwrote the need for a multi-stakeholder guidance framework addressing practical elements related to eIC. According to the stakeholders, a European guidance framework should describe consistent requirements and procedures for implementing eIC on a pan-European level. Generally, stakeholders agreed with the definitions of eIC issued by the European Medicines Agency and the US Food and Drug Administration. Nevertheless, it was raised that, in a European guidance framework, it should be emphasized that eIC aims to support rather than replace the personal interaction between research participants and the research team. In addition, it was believed that a European guidance framework should include details on the legality of eIC across European Union Member States and the responsibilities of an ethics committee in the eIC assessment process. Although stakeholders supported the idea to include detailed information on the type of eIC-related materials to be submitted to an ethics committee, opinions varied on this regard. CONCLUSION: The creation of a European guidance framework is a much needed factor to advance eIC implementation in clinical research. By collecting the views of multiple stakeholder groups, this study advances recommendations that may facilitate the development of such a framework. Particular consideration should go to harmonizing requirements and providing practical details related to eIC implementation on a European Union-wide level.

Testing and Practical Implementation of a User-Friendly Personalized and Long-Term Electronic Informed Consent Prototype in Clinical Research: Mixed Methods Study.

BACKGROUND: Over the years, there has been increasing interest in electronic informed consent (eIC) in clinical research. The user-friendliness of an eIC application and its acceptance by stakeholders plays a central role in achieving successful implementation. OBJECTIVE: This study aims to identify insights for the design and implementation of a user-friendly, personalized, and long-term eIC application based on a usability study with (potential) research participants and semistructured interviews with stakeholders on the practical integration of such an application into their daily practice. METHODS: An eIC prototype was evaluated and refined through usability testing among Belgian citizens and iterative redesign. On the basis of a digital literacy questionnaire, a heterogeneous sample of participants was established. Participants needed to complete a series of usability tasks related to personalization and long-term interaction with the research team while using the "think aloud" technique. In addition, usability tests involved completing the System Usability Scale questionnaire and taking part in a semistructured feedback interview. Furthermore, semistructured interviews were conducted with ethics committee members, health care professionals, and pharmaceutical industry representatives active in Belgium and involved in clinical research. Thematic analysis was undertaken using the NVivo software (Lumivero). RESULTS: In total, 3 iterations of usability tests were conducted with 10 participants each. Each cycle involved some participants who reported having low digital skills. The System Usability Scale scores related to the tasks on personalization and long-term interaction increased after each iteration and reached 69.5 (SD 8.35) and 71.3 (SD 16.1) out of 100, respectively, which represents above-average usability. Semistructured interviews conducted with health care professionals (n=4), ethics committee members (n=8), and pharmaceutical industry representatives (n=5) identified the need for an eIC system that can be easily set up. For example, a library could be established enabling stakeholders to easily provide background information about a clinical study, presented in the second layer of the interface. In contrast, some functionalities, such as informing participants about new studies through an eIC system, were not considered useful by stakeholders. CONCLUSIONS: This study provides insights for the implementation of a user-friendly personalized and long-term eIC application. The study findings showed that usability testing is key to assessing and increasing the user-friendliness of an eIC application. Although this eIC system has the potential to be usable by a wide audience, participants with low digital literacy may not be able to use it successfully, highlighting the need for additional support for participants or other alternatives to an eIC system. In addition, key lessons emerging from the interviews included ensuring that the application is easy to implement in practice and is interoperable with other established systems.

Using provocative design to foster electronic informed consent innovation.

BACKGROUND: The development of technological applications in clinical research, such as electronic informed consent (eIC), is on the rise. The involvement of end users throughout the design process of eIC is of utmost importance to improve the current informed consent process. METHODS: Using a provocative design, we conducted interviews with 30 clinical research participants. Provotypes were used as a starting base to discuss various aspects relevant to eIC. By providing a medium to encourage divergent thinking, participants' views and concerns were solicited. Thematic analysis was undertaken using NVivo. RESULTS: The majority of participants placed trust in the principal investigator or the hospital to perform the role of eIC hosting party. Differing opinions were reported on the amount of information required related to stakeholders' access to an eIC system, and thus, to participants' personal data, to enable trust in an eIC system. Nevertheless, this study indicates a general willingness of participants to share personal data with physicians and pharmaceutical companies on an international level, and to receive requests for new research studies via an eIC system. Participants suggested to tailor an eIC system based upon their preferences, for example, regarding whom they want to share their personal data with. Moreover, they expressed a desire to choose how they can contact the research team, and to indicate which study-related information they would like to receive electronically. In addition, positive opinions were voiced on the integration of a test to assess participants' understanding before providing their eIC. CONCLUSIONS: Following a research through design approach, insights have been generated which inform the design of eIC. Provotypes were designed to help participants think beyond what is familiar to them. Study findings revealed that not all situations were perceived as provocative, because of participants' motivation to advance scientific research and the trust they place in the research team. Nevertheless, the use of provocative design resulted in additional insights, generated by clinical research participants, which could be considered in the further design of eIC.

Personalized and long-term electronic informed consent in clinical research: stakeholder views.

BACKGROUND: The landscape of clinical research has evolved over the past decade. With technological advances, the practice of using electronic informed consent (eIC) has emerged. However, a number of challenges hinder the successful and widespread deployment of eIC in clinical research. Therefore, we aimed to investigate the views of various stakeholders on the potential advantages and challenges of eIC. METHODS: Semi-structured interviews were conducted with 39 participants from 5 stakeholder groups from across 11 European countries. The stakeholder groups included physicians, patient organization representatives, regulator representatives, ethics committee members, and pharmaceutical industry representatives, and all were involved in clinical research. Interviews were analyzed using the framework method. RESULTS: Interviewees identified that a powerful feature of eIC is its personalized approach as it may increase participant empowerment. However, they identified several ethical and practical challenges, such as ensuring research participants are not overloaded with information and offering the same options to research participants who would prefer a paper-based informed consent rather than eIC. According to the interviewees, eIC has the potential to establish efficient long-term interactions between the research participants and the research team in order to keep the participants informed during and after the study. Interviewees emphasized that a personal interaction with the research team is of utmost importance and this cannot be replaced by an electronic platform. In addition, interviewees across the stakeholder groups supported the idea of having a harmonized eIC approach across the European Member States. CONCLUSIONS: Interviewees reported a range of design and implementation challenges which needs to be overcome to foster innovation in informing research participants and obtaining their consent electronically. It was considered important that the implementation of eIC runs alongside the face-to-face contact between research participants and the research team. Moreover, interviewees expect that eIC could offer the opportunity to enable a personalized approach and to strengthen continuous communication over time. If successfully implemented, eIC may facilitate the engagement of research participants in clinical research.

Implementation of Electronic Informed Consent in Biomedical Research and Stakeholders' Perspectives: Systematic Review.

BACKGROUND: Informed consent is one of the key elements in biomedical research. The introduction of electronic informed consent can be a way to overcome many challenges related to paper-based informed consent; however, its novel opportunities remain largely unfulfilled due to several barriers. OBJECTIVE: We aimed to provide an overview of the ethical, legal, regulatory, and user interface perspectives of multiple stakeholder groups in order to assist responsible implementation of electronic informed consent in biomedical research. METHODS: We conducted a systematic literature search using Web of Science (Core collection), PubMed, EMBASE, ACM Digital Library, and PsycARTICLES. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were used for reporting this work. We included empirical full-text studies focusing on the concept of electronic informed consent in biomedical research covering the ethical, legal, regulatory, and user interface domains. Studies written in English and published from January 2010 onward were selected. We explored perspectives of different stakeholder groups, in particular researchers, research participants, health authorities, and ethics committees. We critically appraised literature included in the systematic review using the Newcastle-Ottawa scale for cohort and cross-sectional studies, Critical Appraisal Skills Programme for qualitative studies, Mixed Methods Appraisal Tool for mixed methods studies, and Jadad tool for randomized controlled trials. RESULTS: A total of 40 studies met our inclusion criteria. Overall, the studies were heterogeneous in the type of study design, population, intervention, research context, and the tools used. Most of the studies' populations were research participants (ie, patients and healthy volunteers). The majority of studies addressed barriers to achieving adequate understanding when using electronic informed consent. Concerns shared by multiple stakeholder groups were related to the security and legal validity of an electronic informed consent platform and usability for specific groups of research participants. CONCLUSIONS: Electronic informed consent has the potential to improve the informed consent process in biomedical research compared to the current paper-based consent. The ethical, legal, regulatory, and user interface perspectives outlined in this review might serve to enhance the future implementation of electronic informed consent. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42020158979; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=158979.

Personalized and longitudinal electronic informed consent in clinical trials: How to move the needle?

Changes in the clinical trials landscape have been driven by advancements in digital technology. The use of electronic informed consent to inform research participants and to obtain their consent electronically has the potential to improve participant-researcher interactions over time, facilitate clinical trial participation, and increase efficiency in clinical trial conduct. A personalized electronic informed consent platform that enables long-term interactions with the research team could function as a tool to empower participant engagement in clinical trials. However, significant challenges persist impeding successful and widespread implementation. This Perspective provides insights into the opportunities and challenges for the implementation of electronic informed consent in clinical trials. It sets out key recommendations to promote the implementation of this innovative approach to the informed consent process, including the creation of uniform electronic informed consent platforms at regional and national level.

Digitizing the Informed Consent Process: A Review of the Regulatory Landscape in the European Union.

Background: Rapid technological advancements are reshaping the conduct of clinical research. Electronic informed consent (eIC) is one of these novel advancements, allowing to interactively convey research-related information to participants and obtain their consent. The COVID-19 pandemic highlighted the importance of establishing a digital, long-distance relationship between research participants and researchers. However, the regulatory landscape in the European Union (EU) is diverse, posing a legal challenge to implement eIC in clinical research. Therefore, this study takes the necessary steps forward by providing an overview of the current regulatory framework in the EU, relevant to eIC. Methods: We reviewed and analyzed the key EU regulations, such as the EU General Data Protection Regulation (GDPR) and the Clinical Trials Regulation (CTR). We investigated the legality of eIC in several EU Member States, Switzerland, and the United Kingdom. To this end, we contacted the medicines agencies of various countries to clarify the national requirements related to the implementation and use of eIC in clinical research. Our research was complemented by comparing the legal acceptance of eIC between the EU and the United States. Results: In the EU, a distinction must be made between eIC for participation in clinical research and eIC for processing the participants' personal data, complying respectively with requirements laid down by the CTR and the GDPR. On a national level, countries were classified into three groups: (1) countries accepting and regulating the use of eIC, (2) countries accepting the use of eIC without explicitly regulating it, and (3) countries not accepting the use of eIC. As a result, the regulation of eIC through laws and guidelines shows a large variety among EU Member States, while in the United States, it is harmonized through the Code of Federal Regulations. Conclusion: Various requirements must be considered when implementing eIC in clinical research. Nevertheless, requirements across the EU Member States may differ significantly, whereas, in the United States, efforts have already been made to achieve a harmonized approach.

Co-creation with research participants to inform the design of electronic informed consent.

Objective: This study aimed to provide recommendations for a personalized electronic informed consent interface that is adapted to research participants' needs and could enable a longitudinal interaction between the participants and the research team. Methods: The co-creation process consisted of three co-creation workshops, one focus group discussion, and four semi-structured interviews. In total, 24 participants, who had taken part in four disparate clinical studies in Belgium, were involved. Descriptive statistics and qualitative content analysis were applied to analyze the survey data and audio recordings. Results: Varying perceptions on the type and amount of information described in an informed consent form were reported. Other findings were related to the structure and presentation of information, setting preferences for data sharing, and electronically signing new informed consent versions. Regarding the long-term interaction, most of the participants wanted to receive progress updates, including the results, of the study in which they had taken part. They proposed to receive a notification, preferably via email, in case new information is made available on the electronic informed consent interface. Conclusions: To optimally support the design of an electronic informed consent interface, it is key to understand the research participants' needs. Study findings suggest that an electronic informed consent interface may be a promising technological application to interactively provide study-related information and to keep participants informed during and after the clinical study.

Rethinking informed consent in the time of COVID-19: An exploratory survey.

Background: Owing to the infectious nature of COVID-19, alternative solutions, such as electronic informed consent (eIC), needed to be implemented to inform research participants about study-related information and to obtain their consent. This study aimed to investigate stakeholders' experiences with alternative consenting methods as well as their views on any regulatory or legal guidelines for eIC implementation in clinical research. Results may serve as the cornerstone to rethink the informed consent process in clinical research. Materials and methods: This study consisted of an online survey among three stakeholder groups across European Union (EU) Member States and the United Kingdom. The stakeholder groups included (i) investigators, (ii) data protection officers (DPOs) or legal experts working in the pharmaceutical industry, academia, and academic biobanks, and (iii) ethics committee (EC) members. Data collection occurred between April and December 2021. The data collected were analyzed using descriptive and inferential statistics. Results: The online survey was completed by 191 respondents, of whom 52% were investigators. Respondents were active in 24 out of the 27 EU Member States and the United Kingdom. The majority of each stakeholder group considered validated electronic methods moderately or extremely useful to re-consent previously enrolled research participants upon study amendments or to obtain consent from COVID-19 patients. Nevertheless, this exploratory survey identified that only 13% of DPOs/legal experts, 26% of investigators, and 41% of EC members had experience with eIC. In addition, results suggest that the legal acceptance of eIC across EU Member States and the United Kingdom is variable and that a definition of eIC, issued by national law or policy, is rarely available. The results also showed that the COVID-19 pandemic brought additional challenges to inform participants and to obtain their consent; for example, related to travel restrictions. Conclusion: A number of alternative consenting methods were recommended, for example by the European Medicines Agency, to ensure clinical study continuation during the COVID-19 pandemic. Although stakeholders support the use of eIC in clinical research, it seems that the experience with eIC is low. To harmonize eIC practices as much as possible, further investments in multi-stakeholder, multi-national guidance are needed.

Challenges related to data protection in clinical research before and during the COVID-19 pandemic: An exploratory study.

Background: The COVID-19 pandemic brought global disruption to health, society and economy, including to the conduct of clinical research. In the European Union (EU), the legal and ethical framework for research is complex and divergent. Many challenges exist in relation to the interplay of the various applicable rules, particularly with respect to compliance with the General Data Protection Regulation (GDPR). This study aimed to gain insights into the experience of key clinical research stakeholders [investigators, ethics committees (ECs), and data protection officers (DPOs)/legal experts working with clinical research sponsors] across the EU and the UK on the main challenges related to data protection in clinical research before and during the pandemic. Materials and methods: The study consisted of an online survey and follow-up semi-structured interviews. Data collection occurred between April and December 2021. Survey data was analyzed descriptively, and the interviews underwent a framework analysis. Results and conclusion: In total, 191 respondents filled in the survey, of whom fourteen participated in the follow-up interviews. Out of the targeted 28 countries (EU and UK), 25 were represented in the survey. The majority of stakeholders were based in Western Europe. This study empirically elucidated numerous key legal and ethical issues related to GDPR compliance in the context of (cross-border) clinical research. It showed that the lack of legal harmonization remains the biggest challenge in the field, and that it is present not only at the level of the interplay of key EU legislative acts and national implementation of the GDPR, but also when it comes to interpretation at local, regional and institutional levels. Moreover, the role of ECs in data protection was further explored and possible ways forward for its normative delineation were discussed. According to the participants, the pandemic did not bring additional legal challenges. Although practical challenges (for instance, mainly related to the provision of information to patients) were high due to the globally enacted crisis measures, the key problematic issues on (cross-border) health research, interpretations of the legal texts and compliance strategies remained largely the same.

How to balance valuable innovation with affordable access to medicines in Belgium?

Background: Countries are struggling to provide affordable access to medicines while supporting the market entry of innovative, expensive products. This Perspective aims to discuss challenges and avenues for balancing health care system objectives of access, affordability and innovation related to medicines in Belgium (and in other countries). Methods: This Perspective focuses on the R&D, regulatory approval and market access phases, with particular attention to oncology medicines, precision medicines, orphan medicines, advanced therapies, repurposed medicines, generics and biosimilars. The authors conducted a narrative review of the peer-reviewed literature, of the grey literature (such as policy documents and reports of consultancy agencies), and of their own research. Results: Health care stakeholders need to consider various initiatives for balancing innovation with access to medicines, which relate to clinical and non-clinical outcomes (e.g. supporting the conduct of pragmatic clinical trials, treatment optimisation and patient preference studies, optimising the use of real-world evidence in market access decision making), value assessment (e.g. increasing the transparency of the reimbursement system and criteria, tailoring the design of managed entry agreements to specific types of uncertainty), affordability (e.g. harnessing the role of generics and biosimilars in encouraging price competition, maximising opportunities for personalising and repurposing medicines) and access mechanisms (e.g. promoting collaboration and early dialogue between stakeholders including patients). Conclusion: Although there is no silver bullet that can balance valuable innovation with affordable access to medicines, (Belgian) policy and decision makers should continue to explore initiatives that exploit the potential of both the on-patent and off-patent pharmaceutical markets.

Clinical Research in Neonates: Redesigning the Informed Consent Process in the Digital Era.

Background: Currently, many initiatives are devoted to optimizing informed consent for participation in clinical research. Due to the digital transformation in health care, a shift toward electronic informed consent (eIC) has been fostered. However, empirical evidence on how to implement eIC in clinical research involving neonates is lacking. Methods: Semi-structured interviews were conducted with 31 health care professionals active in Belgium or the Netherlands. All health care professionals had experience in conducting clinical research involving neonates. Interviews were audio-recorded, transcribed and analyzed using the framework method. Results: Interviewees generally supported the use of eIC in clinical research involving neonates. For example, eIC could enable parents to receive study feedback via the eIC system. Requirements were expressed for parental involvement to decide on which feedback would be appropriate to return. Moreover, experts specialized in presenting information and designing electronic systems should be involved. Broad consensus among health care professionals indicates that the face-to-face-interaction between parents and the research team is vital to establish a relationship of trust. Therefore, it is necessary that the use of eIC runs alongside personal interactions with the parents. Concerns were raised about the accessibility of eIC to parents. For this reason, it was suggested that parents should always be given the possibility to read and sign a paper-based informed consent form or to use eIC. Conclusions: Health care professionals' views indicate that the use of eIC in clinical research with neonates may offer various opportunities. Further development and implementation will require a multi-stakeholder approach.

Analysis of illegal peptide drugs via HILIC-DAD-MS.

Biopharmaceuticals have established themselves as highly efficient medicines, and are still one of the fastest growing parts of the health-product industry. Unfortunately, the introduction of these promising new drugs went hand in hand with the creation of a black market for illegal and counterfeit biotechnology drugs. Particularly popular are the lyophilised peptides with a molecular weight of less than 5kDa. Most of them are meant for subcutaneous injection and are easily accessible via the internet. In recent years, different methods based on reversed phase liquid chromatography have been developed to detect and quantify these peptides. The emerging of more polar peptides however requires the introduction of other separation techniques. Therefore, we set out to develop and validate an analytical method based on hydrophilic interaction liquid chromatography (HILIC) to identify and quantify the most frequently encountered illegal peptides on the European market. For this objective, five different HILIC columns were selected and screened for their chromatographic performance. Among those columns, the ZIC HILIC column showed the best performance under the tested screening conditions in terms of resolution and symmetry factor for the targeted peptide set. Hence, the operational conditions were further optimised for the identification of illegal preparations via mass spectrometry (MS) and quantification via UV. Validation was performed via accuracy profiles based on the ISO 17025 guideline. The obtained validated HILIC-method allows for the detection and quantification of the most frequently encountered illegal peptides on the internet in a total run time of 35min including post gradient equilibration and online cleaning step. Combined with a previously developed RPLC-method, the ZIC HILIC system allows for the detection and quantification of a wide spectrum of illicit peptide drugs available on the internet. Furthermore, the developed method could also be envisaged for the detection of new emerging polar peptide drugs.