Herman Pieterse

Since its inception, the process of informed consent has evolved incredibly. However, many barriers remain, preventing the smooth and efficient processes we would like to see in clinical trials (CTs).

The use of electronic informed consent could contribute to overcoming some of these inefficiencies, notably by increasing the flexibility of the process, thus allowing the informed consent document to be better adapted to the patient's needs and facilitating document and process management for study teams. However, the eConsent process is still not widely adopted. We see a number of reasons for this. Firstly, patients are not always comfortable with such technologies. Secondly, the first investment often frightens organizations. Thirdly, countries do not always recognize and allow electronic signatures. Finally, the requirements laid down by regulatory authorities still vary from region to region, country to country, and from one ethics committee to another.

On the opposite, under the increasing digitalization of our world and following the current pandemic, experts claim the necessity of such tool. Many trials had to improvise after the lockdown announcement: sites were suddenly closed, no one could access the documents nor the data, and CRAs were stuck at home.

The recruitment rate of clinical studies, which was already a critical point for trial success, has significantly decreased during this health crisis.

 Patients are stuck at home and cannot come on sites to meet the PI and receive the trial’s information. In addition, the COVID-19 pandemic resulted in a huge shift in the priorities of clinical staff members who needed to focus on COVID units and dedicated clinical trials.

 Consequently, the rate of trials’ enrollment at the end of June 2020 had plummeted from 30% compared with October 2019.

In the recent release (9.0) of “The Medidata Perspective” on the impact of COVID-19 on clinical trials (September 21, 2020), trial sites were asked to evaluate the impact of the pandemic on diverse activities within their studies. On a scale from 1 to 5, the biggest impacts were the sites’ ability to recruit patient (3.02) and to enroll patients (3.02). In response, 39.2% of sites decided to stop recruitment for ongoing trials.

 Nevertheless, this kind of decision is followed by important clinical trial delays and massive expenses.

The eConsent, or digital informed consent, thus appears as a promising solution. More and more CTs stakeholders are showing an interest and are turning to these new tools. Times are changing and we need to evolve with it. For some companies, the digital informed consent is now an integral part of the risk mitigation plan.

However, at the same time, the authorities must ensure that they can judiciously supervise the use of electronic tools. In many cases this calls for a complete revision of existing laws and regulations; it has already been done in the past for some technologies, as for the regulation of electronic signatures, but much more important revisions, such as the 3rd revision of ICH GCP, are underway for the complete integration of the various aspects of emerging technologies.

In the scope of this research project entitled “Toward a global implementation of eConsent in clinical trials”, a survey was conducted to understand how eConsent is perceived and experienced by clinical research experts, how it can improve patient comprehension, reduce site burden as well as to identify areas of opportunities and challenges for further adoption. The survey was based on a prospective questionnaire on eConsent, built to target five types of stakeholders: sponsors, contract research organizations (CROs), ethics committees (ECs), investigational sites (ISs), and vendors of eConsent solutions. The questionnaire was sent to clinical research experts in Belgium, Luxembourg and the Netherlands as, although three bordering European countries, they present disparities in the regulation and acceptance of eConsent.

The survey was sent between September 22, 2020 and November 1, 2020. In total, 342 participations were registered. Of them, 129 were complete responses and 213 were partial responses. Results were analyzed between November 5, 2020 and December 8, 2020.

Overall, the experience with eConsent among the targeted countries and the different stakeholders appeared quite different, but still very low for all of them. On average, 28% of the clinical research experts were novices with eConsent and only 3% had experience. Between the three countries, the Netherlands seemed to be the one with most expertise, followed by Luxembourg and Belgium.

Comparing the stakeholders, each seemed to have a different experience, but overall, very few answered being in full operational usage (~7%). Sponsors were the ones who were most in a pilot phase (~50%). However, half of Sponsors in piloting phase is still very low. The current lack of a uniform regulatory framework around eConsent on a European level appeared to be a rational explanation. In fact, when stakeholders were asked what the main barrier limiting the implementation of eConsent at their organization is, many Sponsors explained that the fragmented guidelines and regulations has considerably hindered their use of eConsent.

Another important barrier that stood out for Sponsors, but also CROs and ISs, was the concern about data privacy and security (~42%). Surprisingly, according to Vendors of eConsent solutions, the main concerns of the customers were not about data privacy but more about the implementation on study sites (50%) and the cost (33%) of such a tool. The site implementation was indeed another important barrier mentioned by the “customer-stakeholders”. However, the cost was evaluated as a hurdle by those in only 12% of the cases.

In a following question, the majority of stakeholders explained that the site implementation wasmore difficult than for a paper-based informed consent (IC) (~61%). In fact, it requires staff training and adaptation and, here again, the fragmented or—in some cases—even lack of regulation around eConsent makes it difficult to implement on sites. However, as one respondent commented, “any change to a normal process is causing difficulties in adapting;” we have to make a first effort if we want to embrace the change and evolution.

Furthermore, this first burden may be worthwhile, as the majority of stakeholders have found that eConsent improves the clinical staff workflow (~70%), facilitates the management of document amendments (~72%), eases the conduct of audits (~80%) and reduces the number of audit findings (~65%). Indeed, the digital aspect of eConsent prevents IC document loss, makes everything available very quickly, facilitates audit trails, and avoids using wrong/old version of the ICF. For the reconsent process, it is also easier to know which patients have not yet consented to the latest version of the ICF. Nevertheless, in order for eConsent to really lighten the workload of sites it needs to be available on multiple devices: vendors’ solutions thus need to be flexible. This will allow the patient to read the information alone and at their own pace, while the staff is busy with other tasks, and to read the information at home, with their family, before deciding whether or not they want to take part in a study.

Another important outcome from the survey was that all stakeholders agreed that eConsent increases the patient understanding of the trial. Indeed, on average, 80% of all stakeholders stated that eConsent allows patients to better understand the trial. Vendor representatives supported this outcome, evaluating the enhanced patient understanding as the most appealing feature of eConsent for customers. This is not surprising as eConsent is first and foremost a patient centric tool. Interactive features and multimedia components like videos and illustrations can be very helpful to simplify and explain difficult information to the patient as shown in the Figure 1 below.

The use of paper-based IC is an important time constraint for the principal investigator (PI) and the site staff who sometimes do not have a lot of time to go properly over the document content with the patient. As one questionnaire respondent noted, with eConsent, “participants will go through the content.”

Among the various eConsent components/features, the ones that apparently have the most impact on this comprehension are the user-friendly interface, visuals, video, and audio. Perhaps these results also indirectly show the reluctance of stakeholders to try new and unknown components and to fully exploit the potential of eConsent.

On the opposite, the components which seems to have the less impact on patient comprehension and engagement are the comment boxes, knowledge assessment and content flags. Indeed, knowledge assessment is considered by many to be too intimidating for study participants. Conversely, according to a Principal Investigator, interviewed for the purpose of this project, asking the participant to answer some questions at the end of the reading/viewing process allows a more pragmatic assessment of the patient's comprehension. The answers to these questions can also be included in a subsequent analysis to identify the overall understanding of the study participants, as well as the IC content section that should be revised to improve understanding. By following the same process, content flags can also be very useful, especially for Sponsors, to identify the "trend" of flags and thus determine which IC section should be modified to provide a better explanation to the participant. Therefore, even though poorly rated, knowledge assessment and content flags can both indirectly help to enhance participant understanding of the study and hence participant engagement in the trial. Those could also constitute proof that all the study participants went through the IC content, understood properly the information, and that all their questions were clarified during their meeting with the clinical staff.

Overall, when asking their opinion on eConsent, all countries were for a broader and global use of this tool, and the majority of stakeholders expressed their growing interest for it following the COVID-19 crisis. On average, 72% of all country representatives were for a broader use of eConsent and 65% of sponsors, CROs, and ISs stated that the recent COVID-19 crisis had increased their interest in this digital tool. They explained that, with the current need for remote visits and speed of starting-up trials, eConsent has become a very attractive solution.

The results from the prospective questionnaire emphasized three important barriers for the implementation of eConsent in clinical trials:

Clinical research experts are missing a dedicated regulatory framework for the implementation and the use eConsent in clinical trials.

People are not educated about the laws and regulations in force and are not educated about the electronic informed consent itself. It appeared in the questionnaire that the inexperienced stakeholders had a less positive opinion towards eConsent, its features, and components.

Indeed, once the people are experienced with eConsent, when it is not an innovation anymore, then the focus is on the processes, the operations and on how to make them as efficient as possible. In the questionnaire, many respondents pointed out the increased difficulty regarding the implementation and day-to-day processes related to the use of eConsent.

Based upon the above findings we can push forward the following recommendations:

The need for a comprehensive, clear and uniform regulation:

A clear legal and regulatory framework for eConsent

Creation of practical and pragmatic guidelines for the implementation of eConsent in clinical trials

Increased continued education and communication:

About the existing and new drafted laws and regulations.

For sites: during the ICH-GCP certification process, an instruction about eConsent and its subtilities might be a good opportunity to educate the sites on this topic.

For ethics committees: training program to educate ECs on eConsent and creation of guidance to standardize the evaluation of eConsent dossier.

Vendors should communicate more about the data protection system and the security of their solution.

Sponsors need to continue to work on lean processes, lean operations to facilitate the implementation and the day-to-day use of eConsent.

Flexibility of Vendors is important: eConsent should be available in several type of devices, simultaneously. In addition, vendors should be able to provide a system to achieve the same "IC amendments" and start-up time as for a paper version of the IC.

Overall, it seems that every clinical research stakeholder has a role to play to truly move the needle of eConsent and increase the implementation of eConsent in CTs.

The prospective questionnaire on eConsent gave interesting insight on the opinions and experiences of eConsent between the three bordering countries as well as between the various stakeholders of clinical research. However, in order to draw more conclusions about eConsent, additional surveys gathering more answers from the three bordering countries but also from the other European Member States would be of great help for the development of a European consortium on eConsent.

, NBCD A/S, Herlev, Denmark & Paris, France, 

, University of Ghent, Heymans Institute for Pharmacology, Ghent, Belgium and Professor, Medical Consultancy B.V. in Heerhugowaard, The Netherlands, 

, Janssen Pharmaceutica NV - Portfolio Delivery Operations, Beerse, Belgium, and 

, University of Namur, Faculty of Medicine, Department of Biomedical Sciences, Namur, Belgium

Mahnke, A. N., Plasek, J. M., Hoffman, D. G., Partridge, N. S., Foth, W. S., Waudby, C. J., Rasmussen, L. V., Mcmanus, V. D., & Mccarty, C. A. (2014). A rural community’s involvement in the design and usability testing of a computer-based informed consent process for the personalized medicine research project. American Journal of Medical Genetics, Part A. 

Grady, C., Ph, D., Cummings, S. R., Rowbotham, M. C., Mcconnell, M. V, Askley, E. A., Phil, D., Kang, G., & Ph, D. (2017). Informed Consent.

Davidson, A., Erana, B., Henry, R, PPD. (2020) Protecting Clinical Research and Patients through Decentralized Trial Strategies. 29/09/2020.

Alsumidaie, M. (2020). Clinical Trial Quality Management: ICH E6 (R2) Interpretations Deepen. Applied Clinical Trials Online.

Medidata Solutions, Inc., a Dassault Systèmes company. (2020) COVID-19 and Clinical Trials: The Medidata Perspective. Release 9.0. 21/09/2020.

Zamora, A., Bernardo, M. (2020). Presentation:” Exceptional Measures?”. 17/07/2020.PPD.

Final Business Plan, ICH E6(R3): Guideline for Good Clinical Practice. (2019). Retrieved from 

https://database.ich.org/sites/default/files/E6-R3_FinalBusinessPlan_2019_1117.pdf

Guffroy, L. (2021). Master Thesis. Towards a Global Implementation of eConsent in Clinical Trials.

Articles

All stakeholders must play part in increasing implementation.