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    7. Decentralized Clinical Trials
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    7. Decentralized Clinical Trials

    • 19 Mins to read
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    7.1 Do the country regulations allow Decentralized Clinical Trials (DCT) elements (e.g., eConsent, ePRO administration, remote investigator site, etc.)?

    Yes.

    7.2 Is there any specific regulation/guidance on the use of DCT elements within a clinical trial?

    Many DCT elements (e.g. eConsent and DTP) have been used in the United Kingdom for years. There is also additional guidance supporting some of these elements, see below:

    7.3 What is the overall acceptability of DCT elements by the British Regulatory Authorities and Ethics Committees?

    It is good, according to a statement from the HRA:

    ”The Health Research Authority (HRA), our partners in the devolved administrations in Wales, Scotland, and Northern Ireland, and the Medicines and Healthcare Products Regulatory Agency (MHRA), support and encourage remote trial delivery where safe and appropriate. Detailed guidance will be issued in due course to support revisions to the clinical trial regulations and ICH-GCP E6”.

    7.4 Has a fully virtual trial (DCT) been conducted in the country yet? If so, please provide an example including the registration number and any link to it, whether COVID/non-COVID trials.

    Yes, as COVID-19 studies have driven much of the increased activity in decentralization, the UK has become an especially popular location for single-country decentralized trials. In the UK, 12% of all single-country trials initiated in the past three years have involved decentralized elements, compared to just 3% between 2010 and 2016. Multi-country trials including the UK have also risen over the timeframe but more slowly, from 4% to 11%. 

    A collaboration between one of the NIHR’s new National Patient Recruitment Centers and UK sponsor company Enteromed has led to rapid recruitment to one of the first fully virtual interventional clinical trials conducted in England. This represented a major step forward in developing the UK’s capacity and capability to conduct virtual clinical research in the current COVID-19 pandemic. 

    Read more about the Relieve IBS-D Trial in this case study investigating the virtual trial design and delivery.

    The UK is also participating in the “Radial” Trials@home study.

    7.5 Are there any non-regulatory DCT initiatives in the country, such as where the investigator sites and local CROs founded an alliance?

    Yes, a prominent alliance is the Decentralized Trials & Research Alliance (DTRA), in which both UK and multinational stakeholders participate. The stated purpose is to “accelerate the adoption of patient-focused, decentralized clinical trials and research within life sciences and healthcare through education and research”.

    7.6 Are there any general considerations when using DCT elements in a study?

    Yes. The Health Research Authority provides the following key considerations for the use of decentralized methods:

    • Sponsors should involve people with relevant experience, including patients, family members, and carers, in the design of trials that apply decentralized methods. This is to ensure assumptions are not made about the locations, methods, or technologies that will work best for participants.
    • Sponsors must assess, verify, and validate the technology, methodology, and usability of any novel digital or other end-points that will be used to collect data directly from participants.
    • Sponsors must do ongoing risk assessment to ensure that decentralized trial methods maximize the benefit to participants, without compromising participant safety and trial oversight. Sponsors should consider factors such as disease, developmental stage of the treatment, administration of the treatment, trial population, and the reliability of assessments.
    • Risk assessments must be clinically informed, and sponsors should consult relevant investigators to address the implications for investigator sites and to ensure that the trial design allows for appropriate investigator oversight.

    eConsent is the use of electronic media (text, graphics, audio, video, podcasts, websites, etc.) via an electronic device to:

    • provide information related to the study and/or
    • document informed consent via an electronic device such as a smartphone, tablet, or computer (eSignatures).

    Electronic Informed Consent - EIC - (eConsent) can be given remotely by patients through a web portal, by e-mail, or by other means after viewing a video or reviewing a consent document online or on paper. The Sponsor, in collaboration with the Investigator, should determine which methods are used to positively identify the patients, collect signatures, and assess their understanding of the consent documents. Prior to the start of the trial, the Sponsor should determine if the use of eConsent is appropriate for the specific trial population.

    eConsent is not simply obtaining a digital signature—it includes a standard workflow involving study education and comprehension checking which sets expectations for the trial participant. In the UK, consent for IP trials also has to include a discussion with an Investigator. This only applies to IMP trials and not non-interventional or observational trials, since this piece of legislation only applies to the MHRA part.

    Questions for Sponsors to consider include: 

    • Are they receptive to the idea?
    • Can they access materials electronically?
    • Do they need a face-to-face explanation?

    The solution will vary between organizations depending on the type of document and the tools available to the person performing the approval (e.g. printer, scanner/smartphone, secure email, third-party software, or existing systems that have tools to capture electronic signatures). There should be a backup process for informed consent in case the electronic system goes down.

    The HRA and MHRA published a Joint Statement on Seeking Consent by Electronic Methods (September 2018) which outlines the expectations for conducting both site-based as well as remote electronic informed consent which should be the basis for eConsent in DCTs.

    With the Medical Research Council (MRC), HRA provides an online tool that gives guidance on consent and the preparation of information for participants. Sponsors ideally should use this to create UK-specific ICFs and steer away from their standard templates and language. Also, they do not expect applicants to simply follow a template, so their guidance will help you design appropriate and proportionate information.

    The online consent guidance - Consent and participant information guidance:

    • Provides information on the principles of consent and how these principles relate to the preparation and use of participant information and consent forms.
    • Proposes recommended content of participant information and consent form as well as information about the design and style of a participant information sheet and consent form.
    • Covers consent in adults, children, young people, and adults not able to consent for themselves (in both emergency and non-emergency) and takes into account UK-wide requirements.
    • Has separate sections that provide examples, templates, and useful links.
    • May be downloaded as a PDF, if required.

    Other resources:

    7.8 Considerations/Requirements for the Use of eSignatures

    According to the Medical Research Council - Recording consent electronically - informed consent must be recorded in writing. However, electronic methods for documenting consent can be considered to be in writing. Sponsors will still need to provide a copy of the signed consent form to the participant and they should consider whether this will be a physical or electronic copy.

    As part of recording consent electronically, you are likely to need to use electronic signatures. Electronic signatures can take a variety of forms and are classified in different ways. You should check what type of electronic signature is acceptable for your research.

    Electronic Signatures:

    The ‘eIDAS’ Regulation (EU) No 910/2014, transposed into UK law via the Electronic Identification and Trust Services for Electronic Transactions Regulations 2016 (SI 2016/696), defines an electronic signature as ‘data in electronic form which is attached to or logically associated with other electronic data and which is used by the signatory to sign’.

    Electronic signatures are classified as:

    • Simple electronic signatures – examples are a stylus or finger-drawn signature, a typed name, a tick box and declaration, a unique representation of characters, and a fingerprint scan.
    • Advanced electronic signatures – these are uniquely linked to the signatory, are capable of identifying the signatory, allow the signatory to retain control, and are linked to data within the signature that can detect any changes made.
    • Qualified electronic signatures – an advanced electronic signature, uniquely linked to the signatory, that is created by a qualified electronic signature creation device, and which is based on a qualified certificate for electronic signatures.

    It is expected that the Sponsor will have a process to ensure that participant identification takes place on remote procedures.

    The MHRA GXP Data Integrity Guidance and Definitions_2018 provides considerations on the expectations and validation requirements of electronic signatures.

    7.9 Considerations/Requirements for Electronic Patient Reported Outcome (ePRO)

    Definition: An electronic patient-reported outcome (ePRO) is where, for example, a hand-held device is used so that the patient can record events such as drug administration, side effects, or adverse events, with the information being uploaded electronically. That is, ePRO systems may replace previously used paper diaries. ePRO methods are most commonly used in clinical trials, but they are also used elsewhere in health care.

    It is expected that data collected via ePRO follows the same GCP standards as any other method of data collection (i.e. that there are processes in place to ensure the quality of the data, and that all clinical information is recorded, handled, and stored in such a way as to be accurately reported, interpreted, and verified). Whether collected by paper or electronic means, the regulatory requirements are that all clinical data should be accurately reported and should be verifiable in relation to clinical trials.

    Functional specifications of such systems should be akin to eCRF (electronic Case Report Form) systems requirements with data management and monitoring processes in place to ensure the accuracy and integrity of the clinical trial data for Electronic Data Capture (EDC) systems such as ePRO, as well as systems used to derive data directly from electronic health records and any devices used to collect clinical data to report to the Sponsor.

    Some of the key considerations when implementing ePRO are the ethical and regulatory requirements of this method of data capture. Although the MHRA has yet to issue specific guidance with respect to ePROs, there have been critical findings in recent MHRA GCP inspections. The GCP inspections metric report of 2018 informed on a case where there was incorrect data in the e-Diary that could not be changed but was used for the analysis and that the e-Diary devices used by subjects did not have an audit trail. Similarly, the MHRA GCP inspection presentation mentions there was concern about insufficient documentation of user acceptance testing for electronic patient diaries.

    The different systems used to collect clinical trial data should be mapped out and the data flow should be defined, in particular the identification and location of source and transcribed data. The functionalities of such systems should permit data changes and authorizations by the investigator with a clear audit trail to verify the integrity of the trial data and to explain why the data was amended.

    The impact of inaccurate data reported through such systems should be assessed for impact on patient safety and data integrity. For example, incorrect weight entered into an IRT system may impact dosing, which has a patient safety impact.

    Incorrect stratification data entered into the IRT system can have an impact on the data analysis and, as such, there should be mechanisms in place to verify the accuracy of the data and report any inaccuracies so that they can be corrected either within the system itself or for the analysis.

    Other resources:

    There is existing guidance available that Sponsors may find useful in relation to expectations on User Acceptance Testing (UAT) for electronic systems in section 14.5 of the MHRA GCP Guide and on the collection of subject data in Chapter 8 of the GCP guide. 

    Overall, GCP inspectors see changes and developments in technology as the future of clinical trials in the UK, enabling the UK to remain at the cutting edge of research. Such technology also leads to the need for new inspection approaches and guidance for stakeholders.

    7.10 Considerations/Requirements for Home Health Care (HHC)- Home Nursing

    Home nursing is permitted in the United Kingdom.

    Mobile nurses will be expected to be trained in the study protocol, be listed in the delegation tasks, and have the appropriate qualifications to conduct the required home procedures.

    Additionally, the HRA will expect that mobile nurses have proper insurance to cover activities outside the site.

    7.11 Considerations/Requirements for HHC - Home Lab Collection

    Collection of biological samples at home may be permitted, as long as the procedures involved do not cause any additional risk to trial participants or to the reliability of the data, and the person performing the task is qualified and/or trained to perform the task. If biological samples are collected at home, it should be considered whether persons taking the sample are qualified and allowed by their local legislation to take the sample. In addition, adequate handling and storage conditions for the samples throughout the entire process should be assured.

    There is an additional training requirement, such as IATA training for handling infections and biological material.

    7.12 Considerations/Requirements for Direct-to-Patient Study Product Delivery

    The clinical trial legislation does not prevent direct-to-participant study products. The MHRA has not posted any specific guidance on this matter; however, they have recommended in the MHRA forum to follow recommendations provided by other authorities such as the EMA’s “Recommendation Paper for Decentralized Elements in Clinical Trials” and FDA’s “Decentralized Clinical Trials for Drugs, Biological Products, and Devices: Guidance for Industry, Investigators, and Other Stakeholders”.

    It is expected that the Sponsor will take a risk-based approach and assess the safety and suitability of IMP to be sent to the participants. 

    7.13 Considerations/Requirements for the Use of Telemedicine

    The use of telemedicine is permitted in the United Kingdom.

    Data privacy is important but being addressed in any case for the individual elements and in the context of healthcare and telemedicine in general. Assuring data integrity requires appropriate quality and risk management systems, including adherence to sound scientific principles. Systems and processes should be designed in a way that encourages compliance with the principles of data integrity, as set out in the MHRA data integrity guidance.

    In particular, data integrity and data flow need to be considered when using digital data collection tools, telemedicine, home visits, and local rather than central laboratories. The Sponsor should consider how to get traceable/auditable data from non-traditional sources into electronic data capture systems. 

    There are two different considerations for telemedicine in clinical trials in the UK. Where telemedicine is simply used in the place of in-person visits/telephone calls and not recorded in any way, the requirements are much less stringent. For example, when telemedicine is used to ask questions to a participant and then these answers are documented in an eSource / eDC / eMR, then this is just using a telemedicine visit in the same way as a face-to-face meeting or telephone call. The issue comes when Sponsors decide that the telemedicine visit itself is the source and needs to be recorded.

    7.14 Considerations/Requirements for the Use of Wearables

    Sources of Real-World Data (RWD) include patient-reported outcomes (PRO) data and data that are collected outside of a clinical study setting such as through wearable devices, specialized/secure websites, or tablets. Sponsors interested in the use of RWD in their development programs are encouraged to engage with the MHRA for further advice on specific proposals. Wearable biosensors should address accessibility for the patient, the clinical study team, and the regulatory agency.

    Digital health includes sensors/wearables and other technologies, such as ingestible devices and implantable. Such devices and apps might be used to collect RWD as part of routine clinical care for patient-reported outcomes or home-based measurements. For example, completing an ‘activities of daily living’ questionnaire online before attending an appointment. It is important that both the device and any tool (such as a questionnaire) are suitably validated for the measurements required. The relevance, objectivity, and practicality of measurements should be considered, taking into account the disease, age, and potential functional abilities of the user. It is also important that only the protocol-required data are transmitted outside of the patient’s device. Some devices may be regulated as a medical device and advice can be sought from MHRA when required.

    The following general principles can be followed:

    • As for all studies, data quality and assurance and appropriate data management oversight are essential.
    • Data quality processes must be detailed in the study protocol and these must be appropriately validated to ensure that any process is fit for its intended use.
    • Data quality checks should be conducted to ensure all data values are recorded, handled, and stored in a way that allows accurate reporting, interpretation, and verification.
    • Data should meet agreed specifications and requirements defined by the Sponsor to support the study requirements to ensure that any received data contains only expected data files and that all data elements are structured correctly as per the agreed specification.

    From March 2025 and beyond, NHS patients will be able to link their wearable devices and other health-related data to their online NHS profile and choose to access 111 online through the NHS App, so the clinical triage has a rich picture of the health history, including any recently uploaded latest health data from the wearable device.

    7.15 Considerations/Requirements for Remote Monitoring

    Remote monitoring is allowed within the United Kingdom. The MHRA has published extensive guidance that provides recommendations and best practices to Sponsors.

    Below is an extract on the “Controls implemented by the Sponsor (or authorized delegated party, e.g. CRO):

    1. The trial monitoring plan should be prepared and/or reviewed by the Sponsor to ensure that a risk-proportionate approach to Source Data Verification/Review is implemented.
    2. Direct access to participant health records is a requirement of monitoring (or auditing) and the Sponsor should already have procedures in place. However, the Sponsor should review these procedures and the Sponsor’s DPIA concerning remote Log-in Access by Monitor (or Auditor) to the EHR system to ensure appropriate controls are in place and the Monitors (or Auditors) are trained in the procedures.
    3. Remote Log-in Access to the EHR system at UK sites must only be undertaken from a physical location in the UK, an EEA state, or another state covered by a UK adequacy decision.
    4. The device through which remote Log-in Access to the EHR system is used should be provided by the Sponsor, or the Sponsor should have undertaken an assessment of the security processes applied to the device(s) of any subcontracted service providers (e.g. CROs, freelance Monitors (or Auditors)). The use of the Monitor's (or Auditor's) own devices is acceptable where approved by the Sponsor. Devices must not be left unattended and accessible when logged into the EHR system.
    5. The Sponsor must not record any video calls where screen sharing of guided direct access or of paper source documentation has taken place. There must be no records of any trial participant information in any “chat” function of the remote video call.
    6. The model clinical trial agreements require that Monitors (or Auditors) are suitably trained to understand information governance requirements. Training courses should be put in place by the Sponsor to protect trial participants’ data confidentiality in relation to the contractual obligations of the Sponsor with the investigator site/institutions.
    7. The Sponsor should ensure through training and employment contracts that all Monitors (or Auditors) comply with information governance requirements.
    8. The Sponsor’s processes and training should include:
      1. Where remote Log-in Access to the EHR system can take place to ensure privacy, for example:
        1. not accessing the EHR system in an open plan office without suitable privacy screens in place on the device;
        2. not accessing the EHR system in a public space or other location where there is a high risk that others who are not authorized could view sensitive information;
        3. if Login Access is from the Monitor (or Auditor) home residence then this should be done privately (i.e., away from family, etc);
        4. the Monitor (or Auditor) should log out of the EHR system prior to leaving the device used unattended (for example, if leaving a desk where a desktop PC is being used, even if log-in to the Sponsor’s system remains).
      2. What is not permitted, for example, taking photographs of the device screen, taking electronic screen images, printing and downloading information from the EHR system, or documenting any information that identifies a trial participant, for example in an email. It should be explicit that sharing user accounts and log-in information for the EHR system with another person is strictly forbidden.
      3. Sharing of the content of the EHR system with anyone other than the Monitor (or Auditor) should be undertaken by the investigator site/Institution personnel and not by the Monitor (or Auditor). For example, the investigator site/institution should provide redacted content from the EHR system to sponsor pharmacovigilance function in relation to queries about a serious adverse event and not the Monitor (or Auditor) sharing their screen/projecting the screen to show EHR system content at a meeting with other Sponsor personnel discussing the SAE. It is acceptable that a Monitor (or Auditor) may need to document information from the medical records that are necessary to record monitoring/audit activities (for example, relating to ineligibility, SAEs); however, the participant must only be identified by their trial identification number.
      4. Actions to take if there is a breach of participant confidentiality (e.g. the circumstances where there is the need to inform the investigator site/institution immediately).
      5. Actions to take if there is a data security breach, for example, if the device used to access the EHR system is lost or stolen, including the possibility to remotely delete all the data content of the device. The Sponsor should provide monitors (or auditors) with contact details of who they should inform if a potential or actual data security breach occurs.
      6. Actions to take if the Monitor (or Auditor) has the ability to or has accessed non-trial participants (i.e., the EHR system restrictions to trial participants have not been implemented accurately or any accidental accessing of the records of non-trial participants).
      7. Ensuring that the investigator site/institution is promptly informed when the user account of the Monitor (or Auditor) is no longer required.
      8. That printed records from the EHR system could only serve as an alternative to direct access if these are certified copies. Inspection findings have shown that this is difficult to achieve, and it is therefore not recommended as an alternative to direct access to the EHR system. Guided access could be considered instead.

    Please refer to Electronic Health Records - MHRA Inspectorate for further information.

    7.16 Considerations/Requirements for Digital Health Technologies (such as Platforms)

    The use of Digital Health Technologies is permitted within the United Kingdom.

    In 2021, the MHRA published “A guide to good practice for digital and data-driven health technologies” with the aim to provide the principles for designing digital and data-driven technology for use in health and care.

    Summary of the key principles:

    • Review the Data Ethics Framework and abide by the principles.
    • Ensure that the product is designed to achieve a clear outcome for users or the system.
    • Ensure that the product is easy to use and accessible to all users.
    • Ensure that the product is appropriately tested and is fit for purpose.
    • Ensure that the product is clinically safe to use.
    • Demonstrate that the product collects, stores, and processes users’ information in a safe, fair, and lawful way.
    • Be fair, transparent, and accountable about what data is being used.
    • Be transparent about the limitations of the data used.
    • Good data linkage will avoid reducing the data quality.
    • Training versus deployment.
    • Make security integra to the design and ensure that the product meets industry best practices security standards.
    • Ensure that the product meets all relevant regulatory requirements.


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