Head of Industry Leaders, Life Sciences and Healthcare, TCS

Hilde Vanaken, PhD

Remote consenting, electronic signatures, I like it, I hate it. Numerous interpretations, various feelings about eConsent. We lost control of what eConsent is about. This article will delve into the fundamental aspects of eConsent to bring it again on track and to the place it deserves.

Whether remote consenting, electronic signatures, or any other electronic consent (eConsent) description, the commonality in all eConsent interpretations is the use of one or more digital features to support the consenting process between participant and investigator. A process that has not changed—all consent process steps are still applicable—but where each consent process step might or not, include one or more digital features as outlined in Figure 1 below.

There is no one size fits all eConsent model. Each disease, each study, each site, each participant might have different needs.

For example, “remote consenting” can be an option but eConsent can also be done entirely in person (at the site, at home). Even without the need of any digitally experienced or digitally equipped participants but by using the site’s electronic device and providing a signed paper copy at the end. Similarly, “electronic signatures” can be an option but signing can also be done on paper (~ wet ink signature) with signed paper upload and/or consent confirmation in the eConsent tool.

“The shorter, the better.” It is not about shrinking the study information into a short and nice-looking summary or video. Participants have the right and must be informed about all the relevant aspects of the clinical trial that they are signing up for.

 Moreover, with the rising use of digital technologies (e.g. wearables, apps) and increasing participants’ responsibilities, the need for extra information is only increasing. Hence, the “length” of the information sharing, should never be the focus.

“Responsibilities have changed”. Adding digital features does not change the responsibilities for the investigator, who still owns the consent process. But similar as with former paper-to-digital transformations (e.g. pCRF to eCRF, PRO to ePRO), eConsent tool validations, certifications, trainings, etc need to be ensured and provided by the sponsor.

“No document anymore”. The consent document is not only the input but also the output and final agreement between participant and investigator. The ability to store and retrieve the document (e.g. by printing, downloading) is a “must have” digital feature of each eConsent tool.

The choice of eConsent digital feature(s) to use for a specific study requires a careful evaluation of the disease, study, sites, and participants upfront. In some cases, the value driver might be limited to the upfront sharing of the consent form using digital communication features, while in other cases it can be an array of digital features such as a glossary, mark unfamiliar flags and a quiz. Incorporation of more eConsent digital features does not necessarily result in more benefits, it all depends on the value drivers for the participant and investigator.

Clearly the COVID-19 pandemic increased the awareness and openness for eConsent, but it also showed that the impact of in-person contacts should not be underestimated.

 The EMA even recommends a face-to-face consent discussion, unless a good justification “why not” was provided and agreed upon.

Equally important, eConsent tools should be simple, self-explanatory, and easy-to-use. If they multiply investigator’s workload or frustrate participants, it will not work. Remember, “bad technology is worse than no technology.”

Besides the value for participants and investigators, eConsent tools might also be beneficial for all stakeholders involved, as illustrated in Figure 2. For example, having insights with one mouse click into accessibility (e.g. who has accessed the participant consent data, and when and why?), optional agreements (e.g. which participant agreed with biosamples, secondary use of data) or the overall consent process (e.g. was the participant able to ask questions, and were they answered?).

Reduced missing or incorrect consent data entries, no wrong versions provided, and less compliance challenges with downstream processes are some other potential values that eConsent might bring. And eConsent can also be the first step to enable broad inclusiveness and diversity by offering any physician, any community worker, etc a tool to introduce what it is all about in line with the capabilities and needs of that specific participant or population group.

All the above aspects should be considered when selecting the eConsent digital features for a disease, study, sites and participants. There is no one size fits all eConsent model. Ultimately, eConsent tools should be flexible and become as easy to use and create as a paper consent.

Bringing eConsent on track through harmonization

As the leader of J&J’s first global eConsent study back in 2013,

 and Transcelerate eConsent project with end deliverables released in 2018,

 it’s hard to gauge where we stand today with eConsent. We need to get back to the basics of what eConsent is about, harmonize terminologies and processes, gain insight in the needs and challenges of key stakeholders and reduce the numerous conflicting messages of acceptance and non-acceptance at a local level.

Hence, I’m extremely proud to lead the non-profit multistakeholder European Forum Good Clinical Practice (EFGCP) eConsent initiative, where we are exactly targeting these hurdles in the industry. The EFGCP eConsent initiative is divided into different workstreams, each with a specific focus area, that will constitute a practical guideline and database (see Figure 3).

A phased stakeholders’ involvement approach was taken, where in the first phase various top leaders from over 50 pharma, vendors, and academic institutes will draft the first deliverables. Next, input of participants, sites, Ethics Committees and Health Authorities will be collected using material tailored to their interests and needs.

Below are some highlights of where the different workstreams stand since they kicked off late end 2022.

 workstream has finalized an eConsent Digital Feature Glossary, including definitions and examples. In some cases, we need to go to the example level to ensure common understanding. For example, in Europe, following eIDAS regulations,

a handwritten signature on an electronic device is an eSignature, while in US, following FDA regulations,

 workstream has launched eConsent Study Docs surveys to get insight into what Health Authorities and Ethics Committees should be informed about (or not), and in which study documents it should be described.

 workstream is developing surveys to get a better understanding of the acceptance/non-acceptance of specific eConsent aspects at the local level. For example, is a handwritten signature on an electronic device allowed, if all identity/authentication methods are identical as with the traditional paper consent process, or which additional measures need to be in place? While the eIDAS Qualified Electronic Signatures is widely accepted in Europe, it might also place a disproportionate burden on both the investigator and the participant and will not always be appropriate, as indicated by some regulatory guidelines.

 workstreams will dive into the needs and challenges of eConsent from each stakeholder group’s perspective. So, moving away from assumptions but bringing in directly the stakeholders' voices, an approach which has already countered common-held beliefs on e.g. physicians’ low referral rates.

 Guidance on measuring, analysis and reporting of value generated by eConsent models with concrete data will also be a focus item, as to date, there are limited publications available that address this.

We are just at the start of this exciting journey to bring eConsent again on track. But with all the enthusiasm and engagements ongoing in the EFGCP eConsent initiative, I trust that as a multistakeholder community, we will achieve our goals and bring eConsent finally to the place it deserves.

Good Clinical Practice - Scientific Guideline 

https://www.ema.europa.eu/en/ich-e6-r2-good-clinical-practice-scientific-guideline

Recommendation Paper on Decentralized Elements in Clinical Trials

https://health.ec.europa.eu/latest-updates/recommendation-paper-decentralised-elements-clinical-trials-2022-12-14_en

Guideline on Computerized Systems and Electronic Data in Clinical Trials 

https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/guideline-computerised-systems-electronic-data-clinical-trials_en.pdf

van Rijssel, T.I.; de Jong, A.J.; Santa-Ana-Tellez, Y.; et al. Ethics Review of Decentralized Clinical Trials (DCTs): Results of a Mock Ethics Review. 

https://www.sciencedirect.com/science/article/pii/S1359644622002963

eConsent: The First Step to Enable Clinical Trial Access to Anyone, anytime, anyplace. 

https://www.appliedclinicaltrialsonline.com/view/econsent-the-first-step-to-enable-clinical-trial-access-to-anyone-anytime-anyplace

eConsent Study Provides Insights to Shape Industry Adoption. 

https://www.appliedclinicaltrialsonline.com/view/econsent-study-provides-insights-shape-industry-adoption

Vanaken, H.; Masand, S.N. Awareness and Collaboration Across Stakeholder Groups Important for eConsent Achieving Value-Driven Adoption. 

https://journals.sagepub.com/doi/full/10.1177/2168479019861924

 Regulation (EU) No 910/2014 of the European Parliament and of the Council of 23 July 2014 on electronic identification and trust services for electronic transactions in the internal market and repealing Directive 1999/93/EC

https://eur-lex.europa.eu/eli/reg/2014/910/oj

Electronic Records, and Electronic Signatures in Clinical Investigations: Questions and Answers 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/electronic-systems-electronic-records-and-electronic-signatures-clinical-investigations-questions

HRA and MHRA Publish Joint Statement on Seeking and Documenting Consent Using Electronic Methods (eConsent). Health Research Authority. September 2018, 

https://www.hra.nhs.uk/about-us/news-updates/hra-and-mhra-publish-joint-statement-seeking-and-documenting-consent-using-electronic-methods-econsent/#:~:text=The%20statement%2C%20which%20is%20supported,consent%20for%20participation%20in%20research.

Getz, K. Rebooting the Statistic that 5% of Eligible Patients Participate in Clinical Trials. 

https://www.appliedclinicaltrialsonline.com/view/rebooting-the-statistic-that-5-of-eligible-patients-participate-in-clinical-trials

Articles

Harmonization and value insights are fundamental to bring eConsent to the place it deserves.

eConsent is Not What You Think

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.

Use of multimedia can improve the consenting process,

 however its broad implementation is still quite limited. Key factors attributed in a recent survey conducted by Transcelerate

 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,

 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,

 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).

 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.

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 research

 or distribution of lay summaries via EMA Clinical Trials Information System (CTIS) that went live in January 2022.

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.

 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 eConsent

 Health Authorities, such as US Food Drug Administration

 and Medicines and Healthcare Products Regulatory Agency;

Ethics Committees such as Belgian Association of Research Ethics Committees

 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 consent

 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!

, PhD, Head of Industry Leaders, Life Sciences and Healthcare, 

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

Awareness and collaboration across stakeholder groups import for eConsent achieving value-driven adoption. Therapeutic Innovative Regulatory Science, 2019, Hilde Vanaken et al.

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/

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

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

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

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/

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

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

Transcelerate guideline, toolkit and landscape assessment, 2017. 

https://www.transceleratebiopharmainc.com/assets/econsent-solutions/

Guidelines for tailoring the informed consent process in clinical trials, 2021, Horizon 2020 funded initiative 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-electronic-informed-consent-clinical-investigations-questions-and-answers

Guidance for sponsors on the use of electronic informed consent in interventional clinical trials in Belgium, 2020. 

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

European Forum Good Clinical Practice (EFGCP) annual conference 2021, Modern problems around informed consent (day 3), 

Understanding differences in studies, sites, and patients are key to making eConsent successful.

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

The COVID-19 pandemic has affected numerous lives globally, pushing the world to adapt and embrace innovative models to ensure continuity of business operations. As we see many countries slowly progressing with the “New Normal,” pharma industry, researchers, healthcare providers are assessing newer digital, virtual approaches which could reinstate the much impacted, clinical trials.

Informed consent, being the first step and hence one of the most critical processes in the clinical trial journey, has also been affected directly by the pandemic, as typically this process is carried out at the site in-person. The impact is not just seen, for new (to-be enrolled) patients, but also, existing patients, who are required to provide re-consents in accordance with the COVID-19 led changes for the study conduct.

In addition to the restrictions for in-person site visit, due to social distancing norms, COVID-19 also brought out some other challenges in areas such as traveling (e.g. impacted public transport) and reduced availability of investigators and site personnel (e.g. increased workload due to COVID-19 requirements).

To overcome the myriad challenges of COVID-19 on clinical trials, an expedited introduction and onboarding of an electronic Consenting tool could be a solution.

The virtual approach will enable sites to connect with patients without the need for in-person visits. Patients too can access the informed consent information at their own pace, read and review the easy-to-understand, multimedia, and interactive material without any pressure and discuss virtually, using telemedicine, any concerns with the investigator prior to providing their electronic signature. Updates to the consent material based on study changes introduced by COVID-19, can also be shared remotely and electronically, and by this maximizing the trial continuity.

For studies already using electronic Consenting but deployed at the site, the shift towards the at home setting will be relatively easy. However, for majority of the studies, using the traditional paper-based process, this shift will require a significant change in way of working.

For Roche, the current COVID-19 scenario imposed an immediate threat having a detrimental impact on many of its ongoing and critical new clinical trials across different therapeutic areas. As a result, the team had to act fast to find a way to ensure business continuity of the impacted trials across all geographies. Rapidly deploying a remote consenting process both for ongoing and new studies, and in compliance with country regulations, could be a solution.

Roche collaborated with TCS ADD team and implemented the TCS Connected Clinical Trials (CCT)—eConsent solution, to quickly rollout the digital informed consent. A close collaboration between both teams was the key to ensure that the application and onboarding process was aligned with Roche’s processes and end user expectations. The eConsent solution, which typically takes three weeks to implement, was deployed in a simplified way and enabled in just seven days. This fast track eConsent model was accessible at home through any medium—laptop, smartphone or tablets, in the patient’s own language.

For sites, the eConsent solution also reduced the administrative workload—something that was highly appreciated in the COVID-19 times—and focus more on patient’s targeted questions and concerns. For patients, being able to review the consent in an easier to understand multimedia format and at their own pace and be better prepared for the conversation with the investigator, was welcomed. Currently, the eConsent solution has already been successfully rolled out for multiple studies across global sites, and many more are being planned.

“With the eConsent technology, our studies will seamlessly address the current challenges of providing access to patients. The response received from the sites so far, is truly positive and paves the way for efficiently onboarding eConsent technologies and virtual trials,” said Mandy Sodhi, Clinical Operations Leader, Genentech (Roche).

Implementation of eConsent involves multiple factors in a typical clinical trial setting. However, considering the huge impact of COVID-19 on new and ongoing studies, dynamic and expedited working models need to be leveraged for catering to specific needs.

Following considerations are crucial for implementing eConsent for studies that require the quickest turnaround time:

Highly configurable tool able to quickly handle various study templates

Device-agnostic intuitive material such as videos, images, infographics, etc. and text

Leverage email or SMS messaging option to share eConsent link.

Access at home from any device, e.g. smartphone, tablet or laptop

Tool with virtual contact feature for site—patient connect

Tool with electronic signature or uploaded of printed signed forms sent via regular mail

Real time insights and oversight across all sites, for all partners

24x7 local helpdesk available for any queries or difficulties

“The implementation model has been the key to onboarding studies impacted by the pandemic and ensures the consent information reaches patients at home. Faster turnaround time for the study setup is providing the much-needed push to re-instate the trial enrollments,” says Ramachandran Prasad, Technical lead for Genentech (Roche).

While COVID-19 has been a dramatic experience, it has also shown that technology and team collaboration can help in navigating the negative impact on clinical trials. The hope is that post COVID-19 pandemic, pharma companies will continue to leverage eConsent and other digital patient centric technologies and move towards real patient centricity.

is the Senior Industry Advisor, TCS Life Sciences and Healthcare (Former Transcelerate eConsent Workstream Leader.) 

http://www.transceleratebiopharmainc.com/wp-content/uploads/2017/11/eConsent-Implementation-Guidance.pdf

As many countries slowly progress with the “New Normal,” researchers and healthcare providers are assessing digital/virtual approaches that could reinstate clinical trials.

Fast Track Implementation of eConsent: COVID-19 Paves the Way for Virtual Trials

A new SaaS platform for clinical trials, soon available to all pharma companies, aims to automate clinical supply, improve patient compliance and enable better medication adherence.


	 
	Equipped with extensive data from its technical pilot study and a newly-forged partnership with global information technology firm Tata Consultancy Services (TCS), Janssen Research & Development, LLC (Janssen) is steadily moving forward with plans to roll out a comprehensive “smart” clinical trial platform in late 2017.

	The platform, known within Janssen as eMeds, includes an array of digital technologies that are brought together by a cohesive software program. It seeks to improve patient engagement while also transforming clinical trial medication supply and data management-with the ultimate goal of enabling more efficient trials that will allow pharmaceutical companies to bring drugs to market faster and cheaper than today.

	The platform currently consists of four modules: eTracking, eLabel, eCommunication and eAdherence. Each addresses a different critical element of the clinical trial process. The platform will be externally branded as Connected Clinical Trials (CCT) and accessible to any pharma company by late 2017 in the form of a software-as-a-service (SaaS) from TCS.

	As a next step, the program will scale up into a larger-scope project, known within Janssen as iSTEP (integrated Smart Trial and Patient Engagement Platform). The next phase will include additional inter-linked features such as eConsent, biometric monitoring, additional means for patient engagement, electronic patient-reported outcomes (ePRO) and electronic clinical outcomes assessment (eCOA).

	In early December, Janssen and TCS are holding an informational cross-pharma meeting for drug development companies at the Janssen offices in Beerse, Belgium; more than 30 people from at least a dozen pharmaceutical companies have confirmed their attendance. The objective of the meeting is to raise overall awareness of CCT, which will begin to roll out next year, and to collect feedback on the ongoing platform development.  
	 
	

	Underlying the platform’s development is an acute understanding of the pharmaceutical industry’s need to transform the clinical supply process on multiple fronts.

	Digital technologies have become more and more embedded in the day-to-day life of patients and investigators, and yet are not currently integrated seamlessly into trials. At the same time, drug sponsors are striving to shorten the timeframe for bringing new drugs to patients; they’re seeking novel ways to facilitate adaptive trial designs and combine multiple studies when appropriate. Another driving factor is the regulatory environment, where regulations are rightfully becoming more stringent in the area of data quality, forcing pharmaceutical companies to rethink today’s largely manual and paper-based processes of managing clinical supplies and tracking patient health data. Not only are these processes time-consuming, but they can result in manual errors.

	Further, poor control over patients’ adherence to medication dosage increases the risk for patient safety during the course of the trial. Yet existing technology tools could be leveraged help monitor adherence and communicate swiftly with patients who may be at risk.

	In addition, pharmaceutical companies need a better system of understanding how clinical supplies are being managed for trials, both at the site and when patients are at home. And they seek to address the challenges of today’s paper-based booklet drug labels. To address these factors, the following four modules are in development:

 is designed to enable registration and verification of all medication kit activities at a clinical site, and help to ensure the right kit is given to the right patient.

 seeks to provide customized, real-time patient notifications via a smartphone, as well as how-to videos and simple tools for adverse event data input. It can also facilitate personalized patient support, providing clarity in medication intake and study procedures.

’s goal is to produce highly readable, patient-specific and all in one electronic drug labels in the patient’s native language. It also enables label flexibility, eliminates booklet printing and decreases waste.

 is designed to ensure registration and improve verification of individual medication intake via sensor-enabled and Near Field Communication (NFC) smart medication packages. The tool is intended to help patients take the right pill at the right time, removing guesswork for medication intake and providing key data for regulatory needs. The data also can serve as an early warning to the company of potential trial drop-outs or safety risk and the opportunity to intervene faster.

All of the modules are designed to connect with one another, and with other databases. Together, they collect participant data and automatically analyze and communicate information to stakeholders, taking the place of paper-based or manual data entries.

	During a trial, the data flows securely from the participant’s smartphone-which collects information from the smart packages and patient entries-to the trial site for review and confirmation. After site reviews the information, certain data fields are uploaded to the clinical database for the sponsor.

	The platform works in various ways to support the patient, providing personalized messages and instructions on what he or she needs to do at specific times throughout the clinical trial. This communication, combined with real-time insight in what the patient is doing at home, offers potential opportunities for adaptive trial design, including real-time dose adjustments or, for adding, changing or dropping a treatment arm based on interim result analysis.
	
	

Technical pilot points to key platform benefits

	The eMeds platform concept has been in the works at the Janssen Research and Development Operations Innovation group for more than five years. During this time, the team has consulted extensively with internal and external stakeholders from related disciplines including clinical, regulatory, supplies, privacy and others.

	But to gain real-life insights on how the various modules actually work in a clinical setting, Janssen orchestrated a technical trial at a Phase I site in Antwerp, Belgium, through which it collected extensive feedback from study participants and site personnel via surveys and interviews.

	The technical study included 24 healthy volunteers, both male and female, evenly representing three age groups: 18-40, 40-65 and older than 65. Volunteers included native speakers of Dutch, French and English. At the outset of the trial, participants were instructed to take one morning capsule and one evening capsule. Three dosing changes were communicated via smartphone over a 12-day period, changing both the quantity of medication as well as the time of day at which it needed to be taken (morning, noon and evening). Patients were aware that dosing changes could occur during the trial, but did not have any further details. The last dose change simulated a medication recall, with all activities occurring at home.

Because this was a technical pilot, a placebo was given; participants were not required to ingest the placebo.

	The study had two objectives. First was to rigorously evaluate the various components of Janssen’s eMeds platform in a clinical setting-testing the integration of databases with the devices and modules, and evaluate real-time communications/actions among all stakeholders. Second was to gauge user-friendliness and satisfaction, from the perspectives of participants, investigators and sponsors. These “softer” measures were significant given that improving patient engagement in clinical trials is a priority for Janssen.

	The trial site personnel received a site user manual, a tablet-based medication scanner and daily compliance reports that showed when each subject pushed out a pill from the smartblister package (a traditional blister package, but with an electronic circuit added on top to track when each pill is popped out). At the site, reports automatically recalculated what each participant had completed (for example, what time each pill was popped out) along with a list of actions that participants still needed to accomplish, and the time window for completing the remaining actions.

	Each trial participant was given a smartphone and charger, a kit with three smartblister packs (each smartblister contained six capsules per day for four days), a quick-reference card, a participant user manual, and two satisfaction questionnaires to be completed on day five and day 12. Each participant also was interviewed individually at the conclusion of the trial. All documents were provided in the individual’s native language.

	As in all trials, all participants were assigned an ID code. In addition, the participant’s language was a required field during registration. An app on the participant’s smartphone was activated and linked to the individual ID so all participant-specific material (for example, how-to videos, notifications) would be pushed to the app in the individual’s native language.

	Before the trial began, all participants were trained on site in a group setting, and received hands-on individual training when the smartphone and smartblisters were provided.
	
	

	The technical pilot was effective in meeting its objectives, shedding light on key benefits of the technology and pinpointing areas for improvement-all of which have been addressed in the latest version of the platform and related smart devices. Among the highlights:

 Despite a stringent treatment regimen, allowing only a 30-minute deviation before or after set dosage times, compliance rate was very high at 92%. The rate slightly decreased throughout the day (95% compliance in the morning, 94% at noon and 89% in the evening) and was higher for females and participants older than 40. When asked what the most important advantages were of the technology, 71% of participants said it was being notified of changes in dosing, and 38% said it was reminders for treatment intake. Some participants suggested adding an additional notification just prior to intake, rather than 15 minutes before, and repeating the eLabel update once more before the next intake.
					 	

elabel seen as a valuable resource for drug information.

 Whereas paper-based drug booklets are commonly returned unopened to trial sites, participants reported that the eLabel functions were a valued resource during the trial and 92% said the updates were easy to understand. Seventy-two% of the participants proactively consulted eLabel’s content, in addition to reading eLabel smartphone notifications. Notably, the final eLabel notification was a medication recall, in which the site and sponsor were able to monitor in real-time whether patients understood the recall via information communicated from their smartblisters.

 A full 100% of participants under 40 said the smartphone was easy to use, as well as 75% of those 40-65 years old and 50% of those older than 65. Only one participant, a women older than 65, reported not liking using smartphones. These results were significant, as only a quarter of participants (all from the youngest age group) reported having prior experience with smartphone and tablet technologies. The smartphones were used to consult dosing instructions, how-to videos, receive several types of notifications (visit reminders, for example) and uploading of smartblister data. Satisfaction with the smartphone increased with usage, as reflected in responses at the start of the trial versus at the end.  

Real-time insight has the potential to bring practical benefits for patient safety.

 The site could immediately interfere when participants missed or took an incorrect dose. This feature could provide immense patient safety benefits as well as pick up early signs of drop out. During the technical pilot, the sponsor was able to monitor the progress of the investigational drug activities, with real-time insight into the site and at home, reducing the need for the sponsor to make in-person visits.  

Immediate insight into patient dosing intake at home may enable adaptive trial design.

 Real-time changes to dosing via eLabel alerts, combined with real-time insight into whether these changes are understood and acted upon as expected, can be an important enabler for supporting patients in complex study designs, as well as adaptive trial design.

Paperless flow achieved, date-entry errors eliminated.

 Databases, devices and stakeholder communications were integrated smoothly, enabling a paperless flow without any data entry during the trial. The process automatically triggered new communications and reminders based on actions, such as when medications were removed from the smart packages.

For participants, uploading data from smartblister to smartphones was a smooth process.

 No one indicated that data upload onto the smartphone took too long, with 54% saying it was very quick and the rest saying it was acceptable. All participants reported it was easy to find the correct location on the smartblister package to upload data. (The location was indicated with an icon that appeared on both the package and smartphone.) Eighty-three% said the whole uploading process was very easy or easy, which is significant given that the majority of participants did not consider themselves experienced with smartphones.     

Sponsor and site personnel feedback was positive.

 The site rated the devices, applications and reports as user friendly, and could achieve 100% remote access to participant’s at-home compliance data. Sponsor had 100% remote access in all activities happening at the site and with the participant, so no in-person visits were needed for reviewing medication-related activities. All stakeholders also said they appreciated the convenience and usability of the apps and quick reference cards.

	Site personnel, sponsor personnel and participants were overall very positive about their experience with the smartphone and smartblister. They noted ease-of-use, clarity and frequency of smartphone notifications, ease of uploading data with smartphone, ease of pushing out capsules, layout of the capsules and on-site training.

	But feedback also brought to light age-related differences. Participants under 65 generally rated all steps of the process as easier and reported a better experience with their smartphones, while older participants were more compliant. Younger participants also commented that the smartphone and smartblister package seemed too large and the hands-on individual training was too long, while the older group said the contrary.

	When participants were asked what they thought was the biggest advantage, they ranked “being notified of changes in dosing” as the most important. This was followed by “reminder for medication intake” and “my doctor has insight into my medication intake.”

	Janssen is now selecting pilots (from among Janssen’s clinical trials) to actively deploy and implement all the different modules of the platform by end-of-year 2017. Once the platform is released, it will be available for other pharmaceutical companies to use.

	Mainstream technology exists today to improve clinical trials in many ways, from tracking adherence data to communicating seamlessly with patients in ways that can help the trial become more flexible and potentially improve patient safety.

	As an industry, we must work to reduce the complexities of clinical trials, from labeling to protocol compliance. The open-format Connected Clinical Trials platform will set us on the path toward this goal, with more engaged trial participants and stronger regulatory data to support innovative new pharmaceutical products. We are on an exciting journey, moving the clinical trial into the digital world, where we will be able to simplify and improve many aspects of the trial while also enhancing important relationships and maximizing the input of patients.  
	
	

Hilde Vanaken, PhD

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