James Gallagher, Products Partner, breaks down some important EU guidance aimed at providing clarity to stakeholders designing and conducting decentralised trials in the EU.

Decentralised trials (DCTs) utilise digital and remote technologies to facilitate clinical trials and collect data from trial subjects outside of trial sites located in traditional clinical settings such as hospitals and laboratories. They can involve the use of digital tools, telemedicine and more mobile and local forms of healthcare such as home health visits, remote monitoring and diagnostics, direct-to-patient shipment of study drugs and electronic informed consent.

While the potential recruitment, retention, time and cost benefits are significant, implementing DCTs in the EU requires careful management of a number of added regulatory challenges.

In this article, we break down some important EU guidance aimed at providing clarity to stakeholders designing and conducting DCTs in the EU.

DCTs: Benefits and challenges

Although they have the potential to address many practical challenges that traditional clinical trials can give rise to, the possible benefits offered by DCTs come with their own set of unique regulatory considerations.

DCTs in the EU

Assessing the appropriateness of decentralised elements as well as detailed planning regarding their actual use require sponsors and investigators to carefully consider various new and unique factors, adherence to EU and national member state laws and regulations, as well as established EU and international standards, guidance and principles related to clinical trials. For example:

• The Clinical Trial Regulation (EU) 536/2014 (CTR) or Clinical Trials Directive 2001/20/EC (CTD) (as applicable)
• ICH E6 (R2) Guideline for Good Clinical Practice (ICH E6) [1]
• EudraLex – Volume 4 – Good Manufacturing Practice (GMP) Guidelines (in particular Annex 13 on manufacture of investigational medicinal products (IMPs))
• Guidelines on Good Distribution Practice (GDP) of Medicinal Products for Human Use
• Guidelines on Good Pharmacovigilance Practices (GVP)
• World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects (2013)
• General Data Protection Regulation (EU) 2016/679 (GDPR)
  

In December 2022, the European Medicines Agency (EMA) and Heads of Medicines Agency (HMA) published a Recommendation Paper on Decentralised Elements in Clinical Trials (the Recommendation Paper) which aims to deliver a non-binding but harmonised perspective on the use of decentralised elements in clinical trials in the EU/EEA.

The Recommendation Paper builds on previous guidance issued during the COVID-19 pandemic and sets out the joint recommendations of the EMA and HMA under a number of headings:

General considerations

Risk assessment: Where decentralised elements are likely to have a significant impact on scientific validity, data integrity, benefit-risk ratio or impact on trial participants’ rights, this should form the basis of a separate documented risk-benefit assessment, with any resulting mitigation actions clearly described in the clinical trial protocol. A summary of the decentralised elements proposed as part of a study should be set out in the cover letter of the clinical trial application to assist in assessment by regulators and ethics committees.

Contingency plans: These should be in place to account for the possible failure of any critical-to-quality decentralised element of the trial such as malfunction of a digital tool or disruption of a planned decentralised visit.

Use of ICT and medical devices: The use of IT devices and systems for the creation and capture of electronic clinical data should be fit for purpose and compliant with the ‘Guideline on computerised systems and electronic data in clinical trials’ EMA/226170/2021. [2] Use of medical devices and IVDs in a clinical trial must ensure compliance with the Medical Devices Regulation (EU) 2017/745 (MDR) and In-vitro Diagnostic Device Regulation (EU) 2017/746 (IVDR) respectively.

Data management: data generated as part of trials using decentralised elements is subject to the same requirements as data from trials using on-site procedures. In order to ensure the scientific quality of data collected, sponsors should carefully scope potential challenges and how they plan to address any challenges introduced via the use of decentralised elements. This becomes particularly important in the case of trials identified as pivotal in marketing authorisation applications.

The role of clinicians: Investigators and healthcare professionals should be involved in study design to ensure the conduct of a DCT in a way that is safe, effective and takes into full account the consequences of having less personal contact with participants and how to best manage related issues around data collection, quality and integrity.

The role of the trial participant: Sponsors and investigators should also involve potential trial participants in the design, development and implementation of a clinical trial involving decentralised elements. This type of consultative approach can lead to enhanced decision making around choice of decentralised elements in a trial, measurement of endpoints that are meaningful to patients and appropriate trial population selection. Any transfer of burden for trial relation procedures to participants that result from the use of decentralised elements must be carefully weighed against the benefits generated.

Informed consent

Although a remote process can be justified in appropriate circumstances, in general, informed consent should be sought during a physical meeting between the investigator and the potential trial participant. Regardless of whether or not all or part of the informed consent process is carried out remotely, the entire procedure for obtaining informed consent still needs to:

• Comply with the relevant principles laid down in the CTR or CTD, ICH E6, the GDPR and national legislation
• Be described in detail in the clinical trial application and the clinical trial protocol
  

Informed consent interviews: If a potential trial participant will not be attending a physical meeting for the informed consent interview, the clinical trial application should address the following:

• The meeting should still take place face-to-face and in real time. Deviation from this convention should be dealt with in the clinical trial application and attending issues like verification of the identity of the parties involved and sufficient understanding of study information should be addressed and justified
• Trial participants and investigators should retain an option to conduct the informed consent interview on-site if requested or deemed necessary by either party. The removal of this on-site option may be justified in certain cases
• As part of the interview process, the investigator should asses the suitability of the use of the decentralised elements of the trial with reference to the proposed participant’s individual circumstances
• Decisions on the format of information relating to the trial that is provided to the potential participant (e.g. use of a digital information leaflet) should be carefully assessed and justified in the clinical trial application, again with reference to the potential participants’ level of comprehension. Likewise, information should be provided to the participant in a storable and retrievable format
• Use of electronic signatures should follow national requirements and guidance on use of e-signatures. Trial participants should be able to download and print a copy of the signed and dated consent form and adapted procedures should be in place to provide for re-consent and follow-up steps via electronic means where necessary
• Where delivery of the IMP to the proposed trial participant forms part of the trial protocol (see below), it should be made clear as part of the informed consent process that contact details will be used for delivery purposes, with further information on use of contact details for this purpose to be set out in participant information materials

Trial procedures at home

The use of a trial participant’s home as a location for carrying out clinical trial activities gives rise to various novel issues that need to be considered by the sponsor and investigator, for example:

• Is a given trial participant’s home suitable? Are there personal or social circumstances that exclude home visits? What type of inclusion/exclusion criteria need to be developed?
• Does the performance of trial related activities in a trial participant’s home give rise to additional risks? Could there be an impact on the reliability of data collected and what type of training and support might the trial participant need to mitigate this?
• The insurance or indemnity covered required by the CTR/CTD should cover any damage resulting from trial related procedures that take place at home
• Because of the reduced number of in-person visits and trial personnel, how will the investigator monitor trial participants and compliance? Trial participants should have the option to meet in-person if needed and should have a direct contact line for when they need instructions, advice or other supports
• Adverse event reporting and management procedures need to be carefully designed and implemented in order to pick up on any safety incidents taking place in the trial participant’s home
• The sponsor should provide alternatives where a trial participant is unable or unwilling to use his or her own smartphone or tablet to collect data

Clinical trial oversight

DCTs will tend to effectively involve an extension of the trial site into participants’ homes potentially using additional service providers such as home-visit nurses and the use of various technologies collecting and delivering data via a number of different routes.

These added variables can lead to an added burden in ensuring that the specific roles and responsibilities of the sponsor, investigator and other parties are clearly defined and that the sponsor and investigator can fulfil their legal obligations under the CTR or CTD, ICH E6 and GDPR.

Service providers: Although some DCTs may involve home visits by healthcare professionals, in accordance with ICH E6 all clinical trial related tasks are the responsibility of either the sponsor or the investigator. Therefore:

• Trial specific tasks that are delegated by a responsible party (investigator or sponsor) to a service provider should be captured in a written agreement
• Delegation of trial specific tasks to additional service providers (including the rationale underpinning same) should also be clearly documented in the trial protocol using a general workflow, with more detail on the extent of their involvement to be included in a protocol related document

Data collection and management

A key feature of DCTs is the increased involvement of trial participants, their caregivers and service providers such as home nurses in data collection activities. However, the addition of these parties as well as the systems needed to ensure that data recorded remains credible, reliable and verifiable (in accordance with ICH E6) adds to the onus on the sponsor to provide for adequate oversight:

• All parties involved in the trial should be provided with an overview of the data flow with the inclusion of a data flow diagram and associated information in the protocol being recommended
• Data acquisition tools should be configured and validated in accordance with their intended use
• Control and complete and continuous access by the investigator to both source data generated either on-site or off-site, as well as source data reported to the lab sponsor (e.g. central lab data) should be ensured
• Have in place adequate security and data integrity measures including use of encryption, firewalls, defined user rights and methods of access, and preservation of metadata

More data to manage: DCTs also create a potential for significantly increased volumes of incoming data, received via a variety of routes and from an increased pool of sources (be they participants, investigators or service providers). Management of this data needs to be informed by a risk-based perspective to effectively identify serious adverse events in a timely manner.

In addition:

• Everyone involved in the trial needs to be properly trained on any digital tools that are to be used, and how to identify, report and manage adverse events that may arise during a trial. Procedures should be developed to deal with the potential for the same adverse event to be reported through several different routes
• Where the generation of critical safety data using digital tools and the use of notifications and alerts is envisaged, the handling of these alerts should be addressed in the trial protocol. Use of a schematic overview of the information flow and respective duties of the parties involved is recommended. The tool that generates the alerts should be tested and validated. A risk mitigation plan needs to be put in place in case the tool does not work as intended

Delivery/administration of investigational medicinal products (IMPs)

Another decentralised element of a clinical trial that can be deployed in appropriate cases involves the delivery and administration of the IMP to the trial participant at home. This gives rise to a further set of issues that need to be factored into design of the trial and which should form the basis of a structured risk assessment.

Delivery: The Sponsor retains overall responsibility for the delivery process (which should be described in the clinical trial protocol or the IMP Dossier) and the various contracts or agreements defining the roles and responsibilities of the parties involved:

• From a risk management perspective, the number of separate transportation steps should be minimised and IMP should only be handed over to the trial participant or their representative or healthcare professional as the case may be, with procedures in place to confirm and record what has been despatched has been successfully delivered
• Vendors used in the delivery process should be authorised to distribute and dispense medicinal products
• The delivery process is subject to national requirements and can take a number of forms, for example:
  – Delivery from the investigator site pharmacy, a delegated pharmacy or a depot
  – Dispensing from a local pharmacy, using a prescription issued by the investigator,, subject to national laws and provided that labelling requirements in respect of IMPs are complied with

Storage and administration: Not all IMPs will be appropriate for storage or administration in a trial participant’s home e.g. where the IMP has specialist or complex storage requirements or requires specialist training and equipment to effectively administer or places a disproportionate burden on the trial participant to ensure compliance with the trial protocol. Generally speaking, if an IMP needs to be administered by a trained healthcare professional, storage and administration might not be possible.

Where storage and administration at home is possible:

• The Sponsor may need to provide trial participants with additional equipment for IMP storage. The investigator should also provide realistic and feasible instructions to the trial participants on use and storage of the IMP. The decentralised storage and administration process should be described in the clinical trial protocol or related documents such as pharmacy manuals and information provided to trial participants
• Where preparation and administration of the IMP by trial participants is envisaged, they will need to be instructed and trained in advance on how to carry out these steps in compliance with the trial protocol. These instructions may need to be tailored to the specific needs of individual patients, and depending on the safety profile of the IMP, the investigator may need to arrange to contact the participant to ensure proper handling during initial preparation and administration, as well as follow up contacts to ensure ongoing compliance with the protocol
• Procedures also need to be in place for return and destruction of unused IMP from trial participants, including in the context of recalls

Conclusion

Digitally-enabled DCTs have the potential to improve recruitment and retention rates among trial participants, streamline processes in appropriate cases, and possibly facilitate new research on conditions and treatments. However, maintaining necessary safety and ethical standards in a more dynamic DCT environment requires very careful planning and management. Given their potential benefits however, stakeholders are encouraged to explore the use of decentralised elements as part of their clinical research activities.

To this end, the Recommendation Paper, as well as draft guidance recently published by the FDA, contains useful information on the particular unique regulatory considerations that should be considered and captured as part of the clinical trial protocol and related documents including contracts and agreements.

For more information, contact a member of our Product Regulation & Consumer team.

The content of this article is provided for information purposes only and does not constitute legal or other advice.

Learn More

• EMA/HMA Recommendation Paper on Decentralised Elements in Clinical Trials (Version 01, 13 December 2022)
• FDA Draft Guidance - Decentralized Clinical Trials for Drugs, Biological Products, and Devices: Guidance for Industry, Investigators, and Other Stakeholders (May 2023)

[1] A draft version of ICH E6 (R3), including an Annex 1 addressing interventional trials, was published in May 2023. Work has also begun on an Annex 2 to this guidance which is intended to address additional considerations for “non-traditional” interventional trials including decentralized studies. ICH expects to be in a position to publish a draft of Annex 2 in the next 12 – 18 months.

[2] A revised version of this guidance was published by the Good Clinical Practice Inspectors Working Group (GCP IWG) on 9 March 2023 and will come into force on 10 September 2023.