Electronic informed consent (eConsent) in clinical research in Europe: opportunities and bottlenecks

Summary: While eConsent has become a reality in the US, Europe is still lagging behind in its implementation. To protect patient rights without compromising on the full potential of clinical research, flexible and dynamic consent formats will be crucial in the future.

Informed consent is a critical element of clinical studies. The guideline for good clinical practice by the European Medicines Agency defines informed consent as „a process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject’s decision to participate” [1]. So far, this process has been managed in a paper-based format, complemented by mandatory educational meetings between the study participant and research staff. With digitalization gaining momentum in the healthcare sector, there is an increased interest of sponsors in digital tools. This includes the implementation of methods for a consent using electronic means (eConsent).

eConsent includes:

„the use of any electronic media (such as text, graphics, audio, video, podcasts, or websites) to convey information related to the study“, and/or
„to seek and/or document informed consent via electronic device such as a smartphone, tablet, or computer.“[2]

eConsent may bring significant opportunities for all involved stakeholders:

Improved participant comprehension may reduce study drop-out:
Standard eConsent improves participant comprehension as shown in a study that compared paper-based consent with eConsent [3]. Specifically interactive and trust-enhanced multimedia components including hyperlinks and factual messages contribute to a better understanding and long-term recall [4]. This in turn might increase participation, adherence and retention, and reduce the risk of study drop-out [5].
Error mitigation and improved workflows:
System integration of eConsent with Electronic Data Capture (EDC), electronic clinical outcome assessment, lab sample management system etc. may reduce the manual work and the susceptibility to errors, e.g. a data flow that connects eConsent information directly to the clinical trial EDC [5,9]. Signature and informed consent form date issues (for example if the investigator signs prior to the patient) are often the reason for regulatory compliance violation. Configuration such as mandatory fields in the eConsent form can address those issues [7]. Data security is a must in this context.
Valuable data insights may improve quality:
As a consequence of the previous point, opt-in/out consent options may be tracked more effectively. Additional data points relevant for evidence generation – within and beyond the trial itself [6] – may be gathered [5]. Regarding the consent process itself, aggregated data may indicate where the consent form needs to be improved, e.g. time spent on reviewing specific sections to identify what elements participants struggle with [5].
Enhanced inclusion and diversity of study participants:
Specifically in the case of (remote) decentralized studies the use of eConsent helps to overcome accessibility barriers as it may allow joining studies remotely. Therefore, under-represented populations could be more likely to join, e.g. rural populations, participants with mobility/frailty issues, childcare responsibilities [8]

Despite obvious advantages resulting from the usage of eConsent, its implementation is still faltering in many European countries.

Some important bottlenecks mentioned in this context include:

Acceptance:
Patients may be reluctant to new technology. There are concerns about overwhelming patients with handling of electronic tools or by providing too much information through eConsent [10, 11]. A Food and Drug Administration (FDA) representative stated that also sponsors and clinical research organizations might be hesitant to innovative approaches due to lacking economic incentives [12]
Concerns about cost-effectiveness:
eConsent implementation might be held back by the fact that the option for participants to choose between paper-based consent and eConsent remains mandatory in most European countries, specifically the part containing the participants’ signature. Clinical study conductors will therefore need to set up the paper-based consent process in any case. A set up of eConsent and double-track process of both, eConsent and paper-based consent, is time consuming and hardly economically reasonable at first sight, especially if it is the initial set up of eConsent [14]
Regulatory barriers, fragmentation and uncertainty:
Regulatory approval of informed consent differs not only across European countries but also on local entity level [13]. This implies that the implementation of eConsent might require additional resources and time. Furthermore, industry and Ethics Commitees representatives claim that guidance on the implementation requirements provided by regulatory entities is lacking [13, 5]. Overall, it can be challenging to find country information about eConsent by regulatory bodies (e.g. Finland and France). As by EU Medical Device Regulation (Article 63) only written informed consent is accepted in all European Countries.

The following table provides an overview of the regulatory landscape of eConsent in some European countries

Country	Regulatory guidelines	Status quo eConsent
Austria	[15]	Acceptance subject to EC
Belgium	[16]	Accepted in addition to paper-based consent
Germany	[18] [19]	Accepted in addition to paper-based consent
Hungary	[20]	Generally not accepted, exceptions released during COVID-19
Italy	no standard on country level [17]	Acceptance subject to EC
Portugal	no standard on country level [21]	Acceptance subject to EC
Spain	no standard on country level [17]	Acceptance subject to EC
The Netherlands	[22]	Accepted in addition to paper-based consent

Future considerations of eConsent

COVID-19 has fast-tracked the adoption of innovative approaches in clinical research that had already been evolving throughout the past decade. Since the outbreak of the pandemic, a remarkable move towards decentralized trials – including eConsent – has taken place. This ensured that clinical research could continue despite the pandemic. Regulatory hurdles were overcome: in the USA, the FDA even actively supported this process by providing an eConsent platform together with guidance documents. COVID-19 circumstances taught us the importance of using resilient tools such as eConsent and contributed to making eConsent in clinical trials a reality.

A survey conducted in the USA shows that its critical mass of adoption is underway with 88% of sites (82% of sponsors respectively) expecting to implement eConsent by the end of 2022, compared to only 28% in 2020 [23]. A reflection on ongoing healthcare research trends makes it clear that the suitable and sensible use of eConsent will be essential in the future to meet the ethical mandate of informed consent. With study designs gaining complexity -e.g. due to data connectivity, real-world-evidence, inclusion of biosamples, individualized therapies etc.- flexible and dynamic consent formats that can process such complexity will be crucial. In this context, a clear regulatory framework will be essential to ensure the protection of patient rights without compromising on the full potential of clinical research.

References:

[1] Guideline for good clinical practice E6(R2). Ema.europa.eu.
https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-6-r2-guideline-good-clinical-practice-step-5_en.pdf.
Published 2016. Accessed January 31, 2022.

[2] Joint statement on seeking consent by electronic methods.
https://s3.eu-west-2.amazonaws.com/www.hra.nhs.uk/media/documents/hra-mhra-econsent-statement-sept-18.pdf.
Published 2018. Accessed January 31, 2022

[3] Rowbotham, M. C., Astin, J., Greene, K., & Cummings, S. R. (2013).
Interactive informed consent: randomized comparison with paper consents. PloS one, 8(3), e58603.

[4] Golembiewski, E. H., Mainous, A. G., Rahmanian, K. P., Brumback, B., Rooks, B. J., Krieger, J. L., … & Harle, C. A. (2021).
An Electronic Tool to Support Patient-Centered Broad Consent: A Multi-Arm Randomized Clinical Trial in Family Medicine. The Annals of Family Medicine, 19(1), 16-23.

[5] Electronic Informed Consent Implementation. Guide Practical Considerations. https://www.eucrof.eu/images/Electronic_Informed_Consent_Implementation_Guide_Practical_
Considerations_Version_1.0_March_2021_2.pdf
Published 2021. Accessed January 31, 2022

[6] Ivanova, D., & Katsaounis, P. (2021).
Real-Time Dynamic Tiered e-Consent: A Novel Tool for Patients’ Engagement and Common Ontology System for the Management of Medical Data. Innovations in Digital Health, Diagnostics, and Biomarkers, 1(2), 45-49.

[7] Bernabe, R. D. L. C., van Thiel, G. J. M. W., Breekveldt, N. S., Gispen-de Wied, C. C., & Van Delden, J. J. (2019).
Ethics in clinical trial regulation: ethically relevant issues from EMA inspection reports. Current medical research and opinion, 35(4), 637-645.

[8] Heller, C., Balls-Berry, J. E., Nery, J. D., Erwin, P. J., Littleton, D., Kim, M., & Kuo, W. P. (2014).
Strategies addressing barriers to clinical trial enrollment of underrepresented populations: a systematic review. Contemporary clinical trials, 39(2), 169-182.

[9] Khairat, S., Ottmar, P., Sleath, B., Welch, B., Qanungo, S., Nichols, M., & Obeid, J. S. (2018).
Facilitating the informed consent process using teleconsent: Protocol for a feasibility and efficacy study. JMIR research protocols, 7(10), e11239.

[10] De Sutter, E., Borry, P., Geerts, D., & Huys, I. (2021).
Personalized and long-term electronic informed consent in clinical research: stakeholder views. BMC medical ethics, 22(1), 1-12.

[11] Sine, S., de Bruin, A., & Getz, K. (2021).
Patient Engagement Initiatives in Clinical Trials: Recent Trends and Implications. Therapeutic Innovation & Regulatory Science, 1-7.

[12] Statement by FDA Commissioner Scott Gottlieb, M.D., on new strategies to modernize clinical trials to advance precision medicine, patient protections and more efficient product development.
https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-new-strategies-modernize-clinical-trials-advance.
Published 2019, Accessed January 31, 2022

[13] van Koningsbruggen-Rietschel, S., Dunlevy, F., Bulteel, V., Hayes, K., Verbrugge, A., Janssens, H. M., … & Downey, D. G. (2021).
Protecting clinical trials in cystic fibrosis during the SARS-CoV-2 pandemic: risks and mitigation measures. Trials, 22(1), 1-7.

[14] Lunt, H., Connor, S., Skinner, H., & Brogden, G. (2019).
Electronic informed consent: the need to redesign the consent process for the digital age. Internal medicine journal, 49(7), 923-929.

[15] FAQ – Regulatory Requirements (GCP)
https://www.basg.gv.at/en/healthcare-professionals/clinical-trials/good-clinical-practice/faq-regulatory-requirements-gcp.
Accessed January 31, 2022

[16] Guidance for sponsors on the use of electronic informed consent in interventional clinical trials in Belgium https://overlegorganen.gezondheid.belgie.be/sites/default/files/documents/guidance_on_use_of_e-icf_vf.pdf.
Published 2020. Accessed January 31, 2022

[17] eConsent Readiness in 12 Countries V10.
https://www.castoredc.com/whitepaper/econsent-readiness-in-12-countries/.
Published 2022. Accessed January 31, 2022

[18] Gesetz über den Verkehr mit Arzneimitteln.
https://www.gesetze-im-internet.de/amg_1976/index.html.
Accessed January 31, 2022

[19] Gesetz zur Durchführung unionsrechtlicher Vorschriften betreffend Medizinprodukte.
https://www.gesetze-im-internet.de/mpdg/index.html.
Accessed January 31, 2022

[20] COVID-19: The NIPN’s Regulatory and Data Protection Guidance on adjustments in clinical trials.
https://www.lexology.com/library/detail.aspx?g=f0507930-5239-47ca-945f-02bdb25dfb89.
Published 2021, Accessed January 31, 2022

[21] Informed Consent.
https://eportugal.gov.pt/en/cidadaos/cuidador-informal/consentimento-informado.
Accessed January 31, 2022

Picture: @Tierney/AdobeStock.com