eConsent—The First Step to Enable Clinical Trial Access to Anyone, Anytime, Anyplace

Introduction

Diversity, inclusivity, and accessibility are the new buzz words in clinical trials. An equitable access to easily understandable, unbiased, and consistent communication of any study for informed decision making is the first and foremost fundamental step for any clinical trial participant.

Consenting is the process of information sharing, discussion, and agreement between an investigator and participant. It is one of the most critical steps in a clinical trial since without an agreement, there won’t be any participation. And it is widely expected that a better-informed trial participant will demonstrate a lower probability of dropping out at a later stage.

Despite criticality of this process, consenting continues to remain a painful, cumbersome, and inefficient process to date. Sites need to spend an enormous amount of time in helping participants understand and paraphrase the complex, lengthy paper consent document. Likewise, participants are put under immense time-pressure to “understand it quickly” and decide, many a times influenced by the “my physician knows best” effect. Wrong versions, missing dates, behind the fact’s signatures are just a few other inefficiencies of the consenting process that is picked up during inspection findings.¹

Use of multimedia can improve the consenting process,² however its broad implementation is still quite limited. Key factors attributed in a recent survey conducted by Transcelerate³ to its low adoption include heavy resource demand to support development, approval and maintenance; regulatory law and privacy constraints and requirements and cost/benefits considerations.

The COVID-19 pandemic significantly increased awareness of eConsent,⁴ however it also led to several misconceptions of what eConsent is about. In a few scenarios, eConsent was even incorrectly correlated with eSignature, resulting in incorrect statements such as “you cannot do eConsent in country A & B”. It isn’t because one feature is not allowed, that we cannot use eConsent to support sites and participants with information sharing, documenting, and creating transparency in the consenting process.

It is absolutely imperative to understand that eConsent is not a new process. The basic principles of consent always remains the same, regardless of the medium used (paper versus digital) or location (in person versus virtual) it is carried out,⁵ as illustrated in Figure 1 below.

Figure 1. Basic principles of consenting process, regardless of media used or location.

Unique considerations for eConsent—authentication, electronic Storage and eSignatures

By its very nature, additional precautions are required to be built in a remote setting to ensure that the trial participant is indeed who he/she is saying they are. Various methodologies can be used to ascertain this, ranging from mimicking the in-person process (e.g. displaying identity card via video conference or upload of identity card) to more sophisticated local authentication systems (e.g. itsme in Belgium). The choice of authentication tool that is acceptable might vary depending on the country, trial, site, etc.

Next, participant also needs to provide consent for electronically storing his/her personal identifiers. In a remote setting, this consent needs to be obtained ‘prior’ to sharing any study related information, and methods e.g., website registration or use of activation code can be leveraged. Electronic storage of participant’s personal identifiers might not be allowed in all countries, or additional requirements (e.g. locally hosted data centers) may need to be met. In such countries where electronic storage is not allowed, the documentation of consent signing, would be limited to a checkbox in the eConsent system.

There are as well wide range of different electronic signatures available (e.g. simple, qualified, and advanced).⁶ The specific type of eSignature allowed can vary on the country, trial, site, etc. Overall guidance provided by multiple stakeholders is to reduce overcomplicating or placing a disproportionate burden on investigator and participant by striving to the most stringent electronic signature highlighted in the Medicines and Healthcare Products Regulatory Agency (MHRA) & Health Research Authority (HRA) eConsent position statement.⁷

The 1st step towards a successful patient-centric trial begins with the right use of eConsent

Use of digital technologies (e.g. apps, wearables, telemedicine) and novel operational model (e.g. virtual coordinating sites, home nurses, couriers) have immense potential to increase diversity, inclusivity, accessibility and embed clinical trials in participants’ personal life.

The new way of conducting clinical trials—also referred to as hybrid or decentralized trials—unfortunately also significantly increase the complexity of clinical trial execution. Thus, the need to support sites to explain what it is all about to their participants has never been more acute. We cannot simply drop “x” additional consent pages covering modern technologies and novel operational models and expect sites to put it in an easy to understand, consistent and non-biased message to participants.

Each participant is as well unique and should have the choice to opt in or out of the proposed technologies and operational models. For example, some participants might not want to opt for telemedicine or want couriers and home nursing to visit their home. These agreements should be captured in the informed consent. When using eConsent, these agreements can even be automatically linked to the underlying supporting tools such as televisits, home nursing, etc., enhancing transparency and overall compliance with participant’s personal choices. Ultimately, the entire process is aimed at enhancing the overall understanding of what participants are truly signing up for.

Reducing data privacy breaches by centralizing patient identifiers

Secure and highly restricted electronic systems can offer increased protective storage for personal identifiers and better control and transparency on who can access the data compared with paper document filings. Moreover, in hybrid and decentralized trials, multiple filings of participant’s personal identifiers might be maintained by various stakeholders (e.g., couriers, home nurses, etc.) that increases the risk of data privacy breaches. Using eConsent, we can eliminate these additional filings and have a “single” secure and highly restricted database for participant’s personal identifiers.

Lastly, the same secure environment can be used to capture participant’s additional personal identifiers (e.g. home address, phone number) or to upload participant’s medical records to enable remote source document verification.

eConsent as an integral part of a clinical trial

Real-time integration with randomization systems ensure that no medication assignments can occur if the consenting process has not been finalized. Consent data can be automatically uploaded in EDC systems and enable reconsenting (or avoid for discontinued participants). Various other data flows, e.g. with laboratory samples, couriers or home nurses systems can increase data quality, data integrity and compliance with participant’s personal choices. Some sites might have their own eConsent system where the focus should be on facilitating seamless integration and avoid any duplication of what is already in place.

It is worth pointing out that eConsent should not be limited to a one-time activity but that certain eConsent features can be re-used throughout the trial conduct to re-iterate to participants on what it is all about or to use snippets of certain assessments prior to an upcoming visit. Long term engagement has been highlighted as another major benefit of eConsent in a recent research study, with callouts to easier reconnects for additional research⁸ or distribution of lay summaries via EMA Clinical Trials Information System (CTIS) that went live in January 2022.⁹

Automation and standardization—key levers to reduce burden and overall cost

Digital technologies require investment—both from a budget and resource perspective. A careful selection of which eConsent feature to include is critical. For example, long-term safety follow-up studies might not require expeStansive video creation, knowledge assessment, etc. compared with more complex studies or studies involving different stakeholders (e.g. assents and parents in pediatric studies).

Also, every participant is different. Some participants prefer detailing, others don’t. Some like reading, others prefer listening (e.g., audio, video). It is strongly advised to involve the target study population and stakeholders upfront in the design and selection of specific eConsent features. Similarly, evidence generation for eConsent is not a one size fits all. Depending on the study, disease, participant population, etc., the suitability and usability of different eConsent features might differ. Key performance indicators—both qualitative and quantitative—need to be included throughout the study execution to generate evidence of what works best for that specific study, population or disease.

Remember that the site-specific consent form in local language remains the final signed and take-home document of the participant. Artificial Intelligence driven data ingestion technologies should also be explored to automatically transform local consent forms in a multimedia format with tiered sections, tabs for site contact details, glossary, stakeholders, etc. Same applies for the reconsenting process. This will also increase compliance and consistency with the take home document as illustrated in Figure 2 below.

Figure 2. Smart eConsent development can reduce burden and overall cost.

Addition of other digital features (e.g. chat box, mark unfamiliar words/phrases) should become as simple as checking a configuration box. And for incorporating more expensive and time-consuming features (e.g. videos, knowledge assessment), standardization and libraries should be introduced to ensure re-use of certain elements for other studies (e.g. explanation of randomization, right to decline at any time).

Site and participants as torchbearers to drive eConsent

The need for improving the consenting process has been a struggle since the start of clinical trials, and has increased exponentially over the last years with the introduction of various technologies and alternative operational models.

eConsent has inspired communities for several years, resulting in various guidelines of cross-industry consortia, such as Transcelerate eConsent¹⁰ and Horizon 2020 iConsent;¹¹ Health Authorities, such as US Food Drug Administration¹² and Medicines and Healthcare Products Regulatory Agency;⁷ Ethics Committees such as Belgian Association of Research Ethics Committees¹³ and Danish National Center for Ethics.¹⁴ The COVID-19 pandemic also added an additional boost in eConsent awareness (even though it led to several misconceptions of what it is about). Despite all these activities, broad implementation of eConsent falls behind.

To be successful and move clinical trials out of the privilege of a select group of people; sites and participants should be put in the driving seat for the development of eConsent. The European Forum for Good Clinical Practice (EFGCP) recently discussed problems around informed consent¹⁵ and is currently exploring to drive broader adoption in eConsent with the right stakeholders as key drivers.

Flexibility, interoperability, automation, and standardization should become fundamental cornerstones if we intend to make eConsent successful. There is no one size fit all. Each participant, each site, each study is different.

We hope everyone joins this journey to make it work, successfully!

Hilde Vanaken, PhD, Head of Industry Leaders, Life Sciences and Healthcare, TCS

References

1. Classification and analysis of the GCP inspection findings. Retrieve from https://www.ema.europa.eu/en/documents/other/classification-analysis-good-clinical-practice-gcp-inspection-findings-gcp-inspections-conducted_en.pdf
2. Awareness and collaboration across stakeholder groups import for eConsent achieving value-driven adoption. Therapeutic Innovative Regulatory Science, 2019, Hilde Vanaken et al.
3. Maturity Survey Results of Transcelerate Modernizing Clinical Trial Conduct (MCTC) initiative, data from 2021. Retrieved from https://www.transceleratebiopharmainc.com/assets/modernizing-clinical-trial-conduct-solutions/
4. No place like home? Stepping up the decentralization of clinical trials. 2021, McKinsey. https://www.mckinsey.com/industries/life-sciences/our-insights/no-place-like-home-stepping-up-the-decentralization-of-clinical-trials
5. Guideline on computerised systems and electronic data in 5 clinical trials
   https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/draft-guideline-computerised-systems-electronic-data-clinical-trials_en.pdf
6. eIDAS Regulaltion: Electronic identification and trust services for electronic transactions in the internal market, July 2014. https://digital-strategy.ec.europa.eu/en/policies/eidas-regulation
7. Medicines and Healthcare Products Regulatory Agency (MHRA) & Health Research Authority (HRA) eConsent position statement, 2018. https://www.hra.nhs.uk/about-us/news-updates/hra-and-mhra-publish-joint-statement-seeking-and-documenting-consent-using-electronic-methods-econsent/
8. Personalized and long-term electronic informed consent in clinical research: stakeholder view. BMC Medical Ethics, 2021. De Sutter et al. https://bmcmedethics.biomedcentral.com/articles/10.1186/s12910-021-00675-7
9. Clinical Trials Information System reaches major milestone towards go-live and application of the Clinical Trial Regulation
   https://www.ema.europa.eu/en/news/clinical-trials-information-system-reaches-major-milestone-towards-go-live-application-clinical
10. Transcelerate guideline, toolkit and landscape assessment, 2017. https://www.transceleratebiopharmainc.com/assets/econsent-solutions/
11. Guidelines for tailoring the informed consent process in clinical trials, 2021, Horizon 2020 funded initiative https://i-consentproject.eu
12. FDA eConsent guideline, 2016. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-electronic-informed-consent-clinical-investigations-questions-and-answers
13. Guidance for sponsors on the use of electronic informed consent in interventional clinical trials in Belgium, 2020. https://barec.be/guidance-for-e-icf/
14. Experimental programme on new informed consent processes in decentralized clinical trials, 2021. Description of VMK's trial scheme for informed consent in decentralized clinical trials
15. European Forum Good Clinical Practice (EFGCP) annual conference 2021, Modern problems around informed consent (day 3), https://efgcp.eu/event.php?eid=42